USP7 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 7
HGNC Gene Symbol
USP7
Identifiers
hgnc:12630 NCBIGene:7874 uniprot:Q93009
Orthologs
mgi:2182061 rgd:1306915
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP7
Number of Papers
700 retrieved on 2023-02-19

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type
MDM2 MDM2 proto-oncogene 0.499 BioGRID IntAct Pathway Commons INDRA (37) Reactome (14) 0.17 0.82 3.76e-02
TP53 tumor protein p53 -0.44 BioGRID IntAct Pathway Commons INDRA (49) Reactome (16) -0.01 -0.16 8.62e-01
PPM1D protein phosphatase, Mg2+/Mn2+ dependent 1D 0.4 Reactome (3) 0.11 0.54 2.79e-01
TP53BP1 tumor protein p53 binding protein 1 -0.377 IntAct INDRA (1) Reactome (3) 0.01 -0.01 8.49e-01
C16orf72 HUWE1 associated protein modifying stress responses 0.359 0.34 1.81 6.71e-04
CDKN1A cyclin dependent kinase inhibitor 1A -0.342 INDRA (5) Reactome (9) -0.01 -0.12 9.48e-01
USP28 ubiquitin specific peptidase 28 -0.331 INDRA (1) Reactome (4) 0.16 0.79 6.28e-03

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP7using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value
GO:0010212 response to ionizing radiation Biological Process 1.61e-10 8.11e-08 9.67e-09
GO:0009314 response to radiation Biological Process 1.68e-10 8.45e-08 9.67e-09
GO:0031570 DNA integrity checkpoint Biological Process 2.24e-10 1.13e-07 9.67e-09
GO:0071478 cellular response to radiation Biological Process 5.69e-10 2.87e-07 1.84e-08
GO:0000075 cell cycle checkpoint Biological Process 1.09e-09 5.47e-07 2.81e-08
GO:0071479 cellular response to ionizing radiation Biological Process 2.68e-09 1.35e-06 5.72e-08
GO:0072331 signal transduction by p53 class mediator Biological Process 3.09e-09 1.56e-06 5.72e-08
GO:0034644 cellular response to UV Biological Process 4.15e-09 2.09e-06 6.71e-08
GO:0071214 cellular response to abiotic stimulus Biological Process 8.08e-09 4.07e-06 1.16e-07
GO:0030330 DNA damage response, signal transduction by p53 class mediator Biological Process 1.37e-08 6.90e-06 1.77e-07
GO:0071482 cellular response to light stimulus Biological Process 2.93e-08 1.48e-05 3.45e-07
GO:0042770 signal transduction in response to DNA damage Biological Process 3.32e-08 1.67e-05 3.58e-07
GO:0009411 response to UV Biological Process 3.97e-08 2.00e-05 3.96e-07
GO:0031668 cellular response to extracellular stimulus Biological Process 5.54e-07 2.79e-04 5.12e-06
GO:0097193 intrinsic apoptotic signaling pathway Biological Process 7.61e-07 3.84e-04 5.80e-06
GO:0002039 p53 binding Molecular Function 7.62e-07 3.84e-04 5.80e-06
GO:0009416 response to light stimulus Biological Process 1.05e-06 5.28e-04 7.54e-06
GO:0072395 signal transduction involved in cell cycle checkpoint Biological Process 1.13e-06 5.69e-04 7.70e-06
GO:0072332 intrinsic apoptotic signaling pathway by p53 class mediator Biological Process 1.27e-06 6.42e-04 8.25e-06
GO:0071496 cellular response to external stimulus Biological Process 1.39e-06 7.02e-04 8.58e-06
GO:0071158 positive regulation of cell cycle arrest Biological Process 1.54e-06 7.77e-04 9.07e-06
GO:0090400 stress-induced premature senescence Biological Process 2.33e-06 1.18e-03 1.31e-05
GO:0071156 regulation of cell cycle arrest Biological Process 3.54e-06 1.79e-03 1.83e-05
GO:0044774 mitotic DNA integrity checkpoint Biological Process 3.44e-06 1.74e-03 1.83e-05
GO:1902807 negative regulation of cell cycle G1/S phase transition Biological Process 6.19e-06 3.12e-03 3.08e-05
GO:0090399 replicative senescence Biological Process 7.57e-06 3.82e-03 3.63e-05
GO:0009267 cellular response to starvation Biological Process 9.52e-06 4.80e-03 4.40e-05
GO:0007093 mitotic cell cycle checkpoint Biological Process 1.27e-05 6.39e-03 5.66e-05
GO:0046827 positive regulation of protein export from nucleus Biological Process 1.75e-05 8.80e-03 7.53e-05
GO:0042594 response to starvation Biological Process 1.84e-05 9.29e-03 7.58e-05
GO:0006367 transcription initiation from RNA polymerase II promoter Biological Process 1.87e-05 9.44e-03 7.58e-05
GO:1902806 regulation of cell cycle G1/S phase transition Biological Process 2.25e-05 1.14e-02 8.84e-05
GO:0071480 cellular response to gamma radiation Biological Process 3.37e-05 1.70e-02 1.28e-04
GO:0010165 response to X-ray Biological Process 3.86e-05 1.95e-02 1.43e-04
GO:0097718 disordered domain specific binding Molecular Function 4.12e-05 2.07e-02 1.44e-04
GO:0007050 cell cycle arrest Biological Process 4.08e-05 2.06e-02 1.44e-04
GO:0006352 DNA-templated transcription, initiation Biological Process 4.34e-05 2.19e-02 1.48e-04
GO:1901988 negative regulation of cell cycle phase transition Biological Process 5.22e-05 2.63e-02 1.73e-04
GO:0044839 cell cycle G2/M phase transition Biological Process 5.46e-05 2.75e-02 1.77e-04
GO:0031647 regulation of protein stability Biological Process 5.90e-05 2.97e-02 1.86e-04
GO:0046825 regulation of protein export from nucleus Biological Process 6.47e-05 3.26e-02 1.99e-04
GO:0044843 cell cycle G1/S phase transition Biological Process 7.04e-05 3.55e-02 2.12e-04
GO:0090068 positive regulation of cell cycle process Biological Process 7.33e-05 3.70e-02 2.15e-04
GO:0070646 protein modification by small protein removal Biological Process 7.48e-05 3.77e-02 2.15e-04
GO:0042771 intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Biological Process 7.84e-05 3.95e-02 2.21e-04
GO:0044389 ubiquitin-like protein ligase binding Molecular Function 8.01e-05 4.04e-02 2.21e-04
GO:2000379 positive regulation of reactive oxygen species metabolic process Biological Process 8.57e-05 4.32e-02 2.31e-04

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP7 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
PYGL glycogen phosphorylase L 7.07e-01 1.63e-08 8.78e-05
IFIT3 interferon induced protein with tetratricopeptide repeats 3 6.41e-01 1.29e-07 3.48e-04
SF3B6 splicing factor 3b subunit 6 4.14e-01 1.98e-07 3.55e-04
MMP1 matrix metallopeptidase 1 3.86e-01 2.87e-07 3.86e-04
DFFA DNA fragmentation factor subunit alpha 5.26e-01 1.37e-06 1.48e-03
PGK1 phosphoglycerate kinase 1 -3.65e-01 3.77e-06 3.38e-03
LDHA lactate dehydrogenase A -3.46e-01 9.03e-06 6.94e-03
USP7 ubiquitin specific peptidase 7 -1.06e+00 1.23e-05 8.27e-03
PTBP1 polypyrimidine tract binding protein 1 6.91e-01 3.52e-05 1.84e-02
S100A2 S100 calcium binding protein A2 -6.33e-01 3.77e-05 1.84e-02
SAA2 serum amyloid A2 -7.78e-01 3.29e-05 1.84e-02
FAM136A family with sequence similarity 136 member A 3.86e-01 4.80e-05 2.16e-02
GLO1 glyoxalase I 3.68e-01 5.70e-05 2.36e-02
MT-ND6 mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 6 -5.88e-01 9.12e-05 3.51e-02
ANKRD1 ankyrin repeat domain 1 3.05e-01 1.45e-04 4.91e-02
IGFBP4 insulin like growth factor binding protein 4 -2.98e-01 1.46e-04 4.91e-02

Gene Set Enrichment Analysis

There were too few differentially expressed genes to run a meaningful GSEA.

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP7 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi minerva creeds ubibrowser acsn | geneways tees gnbr semrep isi trips rlimsp medscan eidos sparser reach
USP7 deubiquitinates TP53. 10 / 75
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Usp7 directly deubiquitinates and stabilises p53, it is also necessary for p53 stabilisation by the tumour suppressor ING1 [XREF_BIBR].
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Because HAUSP can deubiquitinate both p53 and Mdm2, the dynamic consequences are not straightforward.
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While the E3-ligase MDM2 ubiquitinates p53 to induce its proteasomal degradation, HAUSP deubiquitinates P53 and stabilizes the protein.
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Interestingly, in response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from MDM2 mediated degradation of p53 in response to stress.
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This result indicates that ABRO1 specifically facilitates USP7 mediated deubiquitination of p53.
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USP7 deubiquitinates several tumour suppressors (p53, PTEN, FOXO and claspin) and E3 ligases (MDM2, Mule and viral proteins ICP0) and therefore regulates important signalling pathways that are involved in tumorigenesis XREF_BIBR XREF_BIBR.
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The observation that HAUSP can directly interact with and deubiquitylate both p53 and MDM2 creates a conundrum : how can HAUSP stabilize p53 while at the same time being able to stabilize MDM2, which is primarily responsible for the destruction of p53?
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XREF_BIBR - XREF_BIBR USP7 deubiquitinates and stabilizes not only p53, but also Mdm2, the primary E3 ubiquitin ligase of p53 XREF_BIBR, XREF_BIBR Given that both p53 and Mdm2 are known regulators of the steady-level of Poleta, we speculated that changes in cellular USP7 levels may also modulate Poleta level.
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USP7 preferentially deubiquitylates the E3 ligase HDM2 and its binding partner HDMX as well as their substrate p53 (Brooks et al., 2007; Cummins and Vogelstein, 2004; Li et al., 2002, 2004; Meulmeeste[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Further, in vitro assays have shown that MDM2 may act as a bridge so that deubiquitination of p53 by USP7 can occur in the absence of a direct interaction between the two proteins [XREF_BIBR].
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USP7 deubiquitinates MDM2. 10 / 61
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However, Mdm2 can also self-ubiquitylate which promotes its own degradation therefore releasing p53 from its regulatory control, although this is inhibited by USP7, which persistently deubiquitylates Mdm2.
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Thus USP7 would be posited to have opposing effects depending on whether it predominantly deubiquitinates and rescues p53 or MDM2.
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Importantly, HAUSP can deubiquitinate MDM2, MDMX, and p53.
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USP7 deubiquitinates both p53 and MDM2, one of the ubiquitin ligases that ubiquitylates p53, thereby stabilizing both proteins [XREF_BIBR, XREF_BIBR].
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USP7 preferentially deubiquitylates the E3 ligase HDM2 and its binding partner HDMX as well as their substrate p53 (Brooks et al., 2007; Cummins and Vogelstein, 2004; Li et al., 2002, 2004; Meulmeeste[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7, an MDM2 deubiquitinase, deubiquitinates MDM2 and prolongs its half-life to inhibit the p53 tumor suppressor function [XREF_BIBR].
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These contradictory findings were explained by the fact that USP7 could also deubiquitylate MDM2 in some settings, thus indirectly leading to p53 degradation.
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However, HAUSP also deubiquitinates MDM2 and reduction of HAUSP levels, either by RNA interference or by gene deletion, produces a complex phenotype [XREF_BIBR - XREF_BIBR].
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A lack of USP7 dependent deubiquitylation of MDM2 may lead, through enhanced breakdown of MDM2, to accumulation of p53 in melanoma.
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Interestingly, USP7 can deubiquitinate both p53 and its negative regulator HDM2, an E3 ubiquitin ligase responsible for polyubiquitination and subsequent degradation of p53.
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USP7 deubiquitinates Histone_H2B. 10 / 22
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These results are consistent with GMPS stimulating deubiquitylation of H2B by USP7 by forming a stoichiometric complex with USP7 and are inconsistent with GMPS acting catalytically.
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We have observed that USP7 silencing increases H2B ubiquitylation at the FR as well as at LMP1 and Cp promoters and decreases transcriptional activation from the FR element, suggesting that H2B ubiquitylation is inhibitory to transcription controlled by the FR.
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USP7 deubiquitinates H2A and H2B in vitro and changes in Bmi1 and Ring1 ubiquitin levels were reported in USP7 and USP11 overexpression lines.
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This prompted us to investigate whether the human USP7 and GMPS complex also functioned to deubiquitylate histone H2B.
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EBNA1 can also recruit USP7 to EBV sequences that regulate viral gene expression and genome persistence where, in complex with GMP synthetase, USP7 can deubiquitylate histone H2B and affect EBNA1 mediated transcriptional activation XREF_BIBR.
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GMPS enables USP7 dependent deubiquitination of histone H2B resulting in epigenetic silencing [XREF_BIBR - XREF_BIBR].
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In addition to USP22 and its yeast homolog, H2B can be deubiquitylated by USP3 and USP7 in humans.
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The effect of USP7 on deubiquitination of H2A is most likely indirect, since USP7 selectively deubiquitinates histone H2B, but not H2A [XREF_BIBR].
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If the USP7 and GMPS complex functions to deubiquitylate histone H2B, then the loss of this complex from the FR would be expected to increase the level of Ub-H2B in this region.
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GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7.
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USP7 deubiquitinates PTEN. 10 / 19
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However, PTEN is deubiquitinated by USP7/HAUSP and released to the cytoplasm on the PML-RARα signaling network [24].
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XREF_BIBR, XREF_BIBR, XREF_BIBR The DUB USP7 can reverse PTEN monoubiquitylation, affecting its cellular localization; 28 however, to date no DUBs have been described that reverse PTEN polyubiquitylation or otherwise influence PTEN expression levels.
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More recently, the ability of USP7 to deubiquitinate PTEN was found to be under the control of BCR-ABL.
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HAUSP deubiquitinates PTEN to cause its nuclear exclusion, leading to tumour aggressiveness XREF_BIBR.
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HAUSP deubiquitinates monoubiquitinated nuclear PTEN, facilitating nuclear exclusion of PTEN and promoting cancer progression in prostate cancer.
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245 HAUSP (herpesvirus associated ubiquitin specific protease) deubiquitinates PTEN in the nucleus.
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On the other hand, reversal of PTEN monoubiquitination by USP7 (also known as HAUSP) alters PTEN subcellular localization without affecting its protein level [XREF_BIBR].
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We have demonstrated that PTEN monoubiquitination at lysines 13 and 289 is essential for its nuclear localization and tumor suppressive function and, conversely, deubiquitination of PTEN by HAUSP renders PTEN predominantly cytoplasmic.
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A PTEN deubiquitinating enzyme, HAUSP (herpesvirus associated ubiquitin specific protease) may serve in the deubiquitination of PTEN and its shuttling out of the nucleus.
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USP7 deubiquitinates DNMT1. 10 / 12
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Conversely, HDAC1 (histone deacetylase 1) induced DNMT1 deacetylation and HAUSP (herpes virus associated ubiquitin specific protease) modulated DNMT1 deubiquitination to stabilize DNMT1 44.
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We recently showed that USP7 deubiquitinates DNMT1 and functions in concert with several other proteins to regulate DNMT1 stability.
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The UHRF1 and DNMT1 complex has been reported to contain USP7 that deubiquitinates and stabilizes DNMT1 XREF_BIBR, XREF_BIBR.
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Together, these observations suggest that multistep posttranslational modification events may be required to dissociate the UHRF1 and USP7 complex during M phase.Recent evidence has indicated that USP[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Recent evidence has indicated that USP7 also deubiquitinates DNMT1 during S-phase; in late S-phase, acetylation of DNMT1 by Tip60 leads to disruption of the DNMT1 and USP7 complex.
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Importantly, both HDAC3 and USP7 decreased DNMT1 ubiquitination (XREF_FIG, DNMT1 IP).
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FA decreased the ubiquitination of DNMT1 (p = 0.0753), DNMT3A (p = 0.0008) and DNMT3B (p < 0.0001) by decreasing UHRF1 (p < 0.0001) and USP7 (p < 0.0001).
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HAUSP deubiquitinates DNMT1 and protects it from proteasomal degradation.
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Consistent with previous studies that USP7 deubiquitinates and stabilizes DNMT1, knockdown of USP7 in several cell lines (HEK293T, HeLa, HCT116 p53-/- and p53 +/+ cells) resulted in a significant decrease in the DNMT1 protein level, but not in the DNMT1 messenger RNA level (XREF_FIG and XREF_SUPPLEMENTARY).
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USP7 deubiquitinates REST. 10 / 11
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To further address whether REST deubiquitination is directly and specifically mediated by HAUSP, we performed an in vitro deubiquitination assay XREF_BIBR with purified wild-type HAUSP (Flag-Wt-HAUSP), catalytic dead mutant HAUSP (Flag-Mt-HAUSP), or a control deubiquitinase USP1 (Flag-USP1).
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These data further support that REST deubiquitination is specifically mediated by HAUSP.
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Collectively, our data demonstrate that the hTPH2 NRSE-mediated promoter repression via NRSF involves class I HDACs and is modulated by the ubiquitin-specific protease 7-mediated deubiquitination and stabilization of NRSF.
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Wt-HAUSP specifically counteracted beta-TrCP-mediated REST ubiquitination, while the Mt-HAUSP or the control deubiquitinase USP1 did not alter the REST ubiquitination (XREF_FIG), suggesting that HAUSP directly and specifically deubiquitinated REST and suppressed REST ubiquitination.
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We determined that HAUSP physically interacts with REST as demonstrated in co-immunoprecipitation assays (XREF_FIG; XREF_SUPPLEMENTARY), suggesting that HAUSP may mediate REST deubiquitination to prevent REST proteosomal degradation.
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We hypothesized that HAUSP functions as a critical counterbalance to beta-TrCP to inhibit REST ubiquitination and maintain NPCs.
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Collectively, these data demonstrate that HAUSP negatively regulates REST ubiquitination and promotes REST stabilization.
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Our data demonstrate that HAUSP directly deubiquitinates REST.
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Thus, we have identified the consensus HAUSP binding site (310-PYSS-313) on human REST that is required for the HAUSP mediated REST deubiquitination.
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HAUSP knockdown increased REST poly-ubiquitination as demonstrated by both anti-REST immunoprecipitation (IP) and anti-Ubiquitin reciprocal IP (XREF_FIG; XREF_SUPPLEMENTARY).
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USP7 deubiquitinates KAT5. 10 / 11
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Deubiquitination of Tip60 by USP7 determines the activity of the p53-dependent apoptotic pathway.
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USP7 deubiquitinates and stabilizes the acetyltransferase Tip60 to induce p53-dependent apoptotic pathways
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As ATF3 appears to bind to MDM2 as well as p53 XREF_BIBR, XREF_BIBR, the observation that ATF3 promoted USP7 mediated deubiquitination of Tip60 suggests a possibility that ATF3 might also regulate the MDM2 or p53 stability through regulating USP7 in the DNA damage response.
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ATF3 promotes USP7 mediated deubiquitination of Tip60.
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As ATF3 alone did not appear to decrease the Tip60 ubiquitination level (XREF_FIG, lane 3), these results argue for the notion that ATF3 promoted USP7 mediated deubiquitination of Tip60 thereby stabilizing the latter protein.
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Deubiquitination of Tip60 by USP7 determines the activity of the p53-dependent apoptotic pathway.
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Rather, we found that ATF3 promoted USP7 mediated deubiquitination of Tip60 thereby diminishing Tip60 ubiquitination required for proteosomal degradation.
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In addition, utilizing the UbiTest analysis we demonstrate that inhibition of USP7 increases polyubiquitination of Foxp3, Tip60 and USP7.
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Here we show that USP7 interacts with and deubiquitinates Tip60 both in vitro and in vivo.
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USP7, a dominant deubiquitinating enzyme in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinates Tip60 both in intact cells and in vitro and increases Tip60 protein levels.
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USP7 deubiquitinates FOXP3. 10 / 10
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On the other hand, the deubiquitinase USP7 is able to deubiquitinate FOXP3 in an HSP90 dependent manner and stabilizes FOXP3 to increase Treg number to enhance Treg suppressive activity.
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USP7 Associates with and Deubiquitinates Foxp3.
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Furthermore, cambogin (10 μM) prevented Foxp3 loss in human primary Treg cells in vitro, and promoted USP7-mediated Foxp3 deubiquitination and increased Foxp3 protein expression in LPS-treated cells.
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To determine whether USP7 could also deubiquitinate Foxp3, we analyzed Foxp3 polyubiquitination in transfected HEK 293T cells.
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E3 ubiquitin ligase Stub1 induces the K48 polyubiquitination and degradation of Foxp3, whereas deubiquitinase USP7 decreases Foxp3 polyubiquitination and increases Foxp3 expression XREF_BIBR.
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USP7 mRNA expression was significantly upregulated in iTreg cells but not in other Th subsets, further supporting a role for the USP7 deubiquitination of Foxp3 in Treg cell differentiation (XREF_FIG).
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In a previous study, van Loosdregt et al. (2013) showed that USP7 interacted with and deubiquitinated Foxp3, thereby increasing Foxp3 protein levels.
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Conversely, the DUB Usp7 deubiquitinates and stabilizes Foxp3 to promote Treg functions.
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In addition, utilizing the UbiTest analysis we demonstrate that inhibition of USP7 increases polyubiquitination of Foxp3, Tip60 and USP7.
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Foxp3 polyubiquitination was reduced with ectopic expression of USP7, indicating that USP7 can directly deubiquitinate Foxp3 (XREF_FIG).
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USP7 deubiquitinates MDM4. 10 / 10
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USP7 preferentially deubiquitylates the E3 ligase HDM2 and its binding partner HDMX, resulting in the destabilisation of p53 and the repression of p53 transactivation activity (Refs 43, 44, 45).
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Subsequently, HAUSP was shown to deubiquitinate Mdm2 and Mdmx, thereby stabilizing these proteins.
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More recent data suggest that Hausp also deubiquitinates Mdm4, another inhibitor of p53 activity.
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Additionally, Wip1 inhibits p53 through MdmX and enhances the interaction of MdmX with ubiquitin specific peptidase 7 (USP7), which deubiquitinates and stabilizes MdmX.
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Additionally, Mdm2, MdmX and p53 can be deubiquitinated by the HAUSP (herpesvirus associated ubiquitin specific protease) protein.
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Importantly, HAUSP can deubiquitinate MDM2, MDMX, and p53.
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MdmX phosphorylation (A38) inhibits (A40) the deubiquitination (A39) of MdmX by Hausp, which in turn increases ubiquitinated MdmX showing coherent regulation by DNA damage induced kinases.
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HAUSP can also deubiquitinate and stabilize MdmX and has a role in DNA damaged induced degradation of MdmX [XREF_BIBR].
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Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.
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USP7 deubiquitinates CTNNB1. 10 / 10
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Conversely, USP7 promotes deubiquitination of beta-catenin with RNF220, which is a RING domain E3 ligase, and upregulates the Wnt signaling pathway [XREF_BIBR].
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Indeed, CRISPR targeting of USP7 in the CID deleted APC4 cells readily restored beta-catenin ubiquitination in the destruction complex (XREF_FIG D and XREF_SUPPLEMENTARY I).
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Moreover, ZMIZ2 recruits the enzyme USP7, which deubiquitylates and stabilizes beta-catenin, thereby facilitating colorectal tumorigenesis.
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USP7 Is a Tumor-Specific WNT Activator for APC-Mutated Colorectal Cancer by Mediating β-Catenin Deubiquitination
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Specifically, USP7 binds the N-terminus of β-catenin when the APC losses CID confirming the essential role of USP7 in the activation of Wnt signalling and cell survival in colorectal cancers.13 Ma et al showed that the USP7/RNF220 complex activates the Wnt pathway while knockdown of USP7 using a small interfering RNA (siRNA) strategy, reduces the expression of Wnt.18 Conversely, a recent study proposed that USP7 deubiquitinates β-catenin and RNF220 independently and works as a tumour-specific condition when APC is mutated.
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USP7 Depletion in APC Truncated CRC Cells Suppresses Aberrant Wnt Activation by Restoring beta-Catenin Ubiquitination.
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Ubiquitin specific peptidase 7 (USP7) mediates deubiquitination of beta-catenin and enhances canonical Wnt signaling [XREF_BIBR].
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Together, our data imply that USP7 interacts with the N terminus of beta-catenin directly to mediate beta-catenin deubiquitination when APC is mutated.
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The RNF220 and USP7 complex deubiquitinates beta-catenin and enhances canonical Wnt signaling.
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USP7 Interacts with the N Terminus of beta-Catenin Directly to Mediate beta-Catenin Deubiquitination.
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USP7 deubiquitinates ERCC6. 9 / 9
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While both CSB and UV stimulated scaffold protein A (UVSSA) exhibit a biphasic decrease and recovery upon UV irradiation, only CSB recovery depends on USP7, which physically interacts with and deubiquitinates CSB.
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Additional factors continue to be identified : Examples include NEDD4, that is implicated in DNA damage induced ubiquitination of the RNA polymerase II subunit RPB1 to mark it for proteosomal degradat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Upon transcription arrest, these factors bind strongly to RNAPII, and USP7 deubiquitinates CSB to stabilize it.
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Upon transcription arrest, these factors bind strongly to RNAPII, and USP7 deubiquitylates CSB to stabilize it.
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Additional factors continue to be identified : Examples include NEDD4, that is implicated in DNA damage induced ubiquitination of the RNA polymerase II subunit RPB1 to mark it for proteosomal degradation; UVSSA and USP7 that bind to RNAPII upon transcription arrest and deubiquitinate CSB to prevent its degradation; and the SPT16 FACT chromatin remodeler.
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Upon transcription arrest, these factors bind strongly to RNAPII, and USP7 deubiquitylates CSB to stabilize it.
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To avoid premature degradation of CSB, UVSSA, which binds firmly to stalled RNA pol II, recruits USP7, an enzyme that promotes deubiquitination of CSB, highlighted in blue in XREF_FIG.
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Here, we demonstrate that USP7 deubiquitinates CSB to maintain its levels after ultraviolet (UV)-induced DNA damage.
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USP7 deubiquitinates HIF1A. 8 / 8
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USP7, also known as HAUSP (herpesvirus associated ubiquitin specific protease), deubiquitinates HIF-1alpha and stabilizes it.
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Beyond, USP7 deubiquitinates and stabilizes HIF1alpha, PHF8 could regulate HIF1alpha through USP7 [XREF_BIBR].
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K63 polyubiquitinated HAUSP deubiquitinates HIF-1alpha and dictates H3K56 acetylation promoting hypoxia induced tumour progression.
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Since both HAUSP and HIF-1alpha play a significant role in tumour progression and aggressiveness XREF_BIBR XREF_BIBR, we evaluated whether HAUSP could deubiquitinate HIF-1alpha through interacting with HIF-1alpha.
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HAUSP interacts with and deubiquitinates HIF-1alpha.
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Beyond, USP7 deubiquitinates and stabilizes HIF1alpha, PHF8 could regulate HIF1alpha through USP7 [49].
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These results demonstrate that HAUSP decreases HIF-1alpha ubiquitination through recognizing a consensus sequence located in HIF-1alpha.
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K63-polyubiquitinated HAUSP deubiquitinates HIF-1a and dictates H3K56 acetylation promoting hypoxia-induced tumour progression.
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USP7 deubiquitinates TPP1. 7 / 7
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Together, these data indicate that USP7 deubiquitinates TPP1.
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Addition of USP7 (WT)-3xFLAG but not USP7 (C223S)-3xFLAG reduced TPP1 ubiquitination (XREF_FIG C, lanes 5 and 6), confirming that TPP1 is a USP7 substrate.
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We identify amino acids in TPP1 and USP7 that are critical for their interaction and multiple lysines within TPP1 that are oligo ubiquitinated and deubiquitinated by USP7.
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Therefore, both in vivo and in vitro evidence indicates that TPP1 is deubiquitinated by USP7.
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TPP1 Is Deubiquitinated by USP7.
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Because TPP1 is ubiquitinated and the co-immunoprecipitation data suggested that it is a USP7 substrate, we next tested whether USP7 indeed deubiquitinates TPP1.
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USP7 deubiquitinates RNF2. 7 / 7
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Taken together, these data indicate that USP7 specifically deubiquitinates RING1B in vitro.
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In order to confirm that USP7 mediates the deubiquitination of RING1B, we added to self ubiquitinated RING1B bacterially expressed purified His 6 -USP7 and its inactive mutant His 6 -USP7 C223S.
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Although, USP7 directly and specifically deubiquitinates RING1B in vitro and in vivo, it does not discriminate between the activating and proteolysis targeting modes of ubiquitination, and therefore has a stabilizing effect on RING1B.
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USP7 deubiquitinates ubiquitinated (by itself or external ligase such as E6AP) RING1B ligase of the polycomb complex [XREF_BIBR].
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As shown in Fig. 4 C, USP7 is not a chain type specific DUB and it can deubiquitinate different lysine based polyubiquitin chains.Based on our observation that USP7 can reverse E6-AP-mediated ubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Here we identify USP7 as a deubiquitinating enzyme that regulates the ubiquitination state of RING1B.
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It is possible that in wild type spermatocytes, USP7 may directly deubiquitinate RNF2 and thus reduce H2A ubiquitination in the XY body.
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USP7 deubiquitinates NFkappaB. 7 / 7
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NFkappaB can be directly deubiquitinated by HAUSP 87 or can be indirectly regulated by deubiquitination of its upstream factors, such as TRAF6, 24 NEMO (IKK-gamma) XREF_BIBR, XREF_BIBR (HSCARG interacts with NEMO to suppress its polyubiquitination by recruiting HAUSP 91), NIMA (Never In Mitosis Gene A)-related kinase 2 (Nek2), a centrosomal serine/threonine kinase (HAUSP stabilizes Nek2 leading to activation of NFkappaB pathway in multiple myeloma).
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USP7 deubiquitination of NF-kappaB leads to increased transcription.
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Therefore, USP7 's deubiquitination of NF-kappaB enhances pro cytokine production when induced by the TLR signaling pathway.
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This analysis reveals a significant and selective inhibition of NF-kB target gene expression following TLR4 activation and strongly supports the inhibition of USP7 deubiquitination of NF-kB as a potential therapeutic strategy.
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Moreover, USP7 deubiquitination of NF-kappaB subunits leads to the increase of transcriptional activity, suggesting this may be the mechanism by which P22077 inhibits H 2 O 2 -induced USP7 mRNA expression.
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It has been reported that deubiquitination of NF-kappaB by USP7 is essential for TLR- and TNFR induced gene expression [XREF_BIBR], thus USP7 may has a positive feedback in regulating TNFR1 and also circ-DB formation.
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These findings reveal a unique mechanism controlling NF-kappaB activity and demonstrate that the deubiquitination of NF-kappaB by USP7 is critical for target gene transcription.
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USP7 deubiquitinates SPRTN. 6 / 6
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USP7 deubiquitinase deubiquitinates SPRTN upon DPC induction, antagonizing the autocatalytic cleavage and subsequent inactivation of SPRTN.
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Upon formaldehyde treatment and other yet to be identified signals, SPRTN is deubiquitinated by USP11 (this study), USP7, and VCPIP1.
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USP7 deubiquitylates SPRTN upon DPC induction.
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Recently, it was shown that USP7 deubiquitinates SPRTN, preventing SPRTN auto-cleavage upon DPC induction.
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Upon DPC induction, SPRTN is deubiquitinated by USP7, promoting SPRTN stability.
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showed that deubiquitination of SPRTN by USP7 does not govern SPRTN localization on chromatin.
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USP7 deubiquitinates CHEK1. 6 / 6
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Here we identified ZEB1 as an ATM substrate and the mechanism underlying the association between EMT and radioresistance (XREF_FIG) : in response to IR, ATM kinase is activated, which phosphorylates and stabilizes ZEB1; ZEB1 in turn interacts with and promotes the activity of USP7, which deubiquitinates and stabilizes CHK1.
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68 HAUSP deubiquitinates checkpoint kinase Chk1, 69 its activator Claspin, 70 and checkpoint with forkhead and RING finger domain protein (Chfr).
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Mechanistically, LINC02582 interacts with deubiquitinating enzyme ubiquitin specific peptidase 7 (USP7) to deubiquitinate and stabilize checkpoint kinase 1 (CHK1), a critical effector kinase in DNA damage response, thus promoting radioresistance.
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Mechanistically, LINC02582 interacts with deubiquitinating enzyme ubiquitin specific peptidase 7 (USP7) to deubiquitinate and stabilize checkpoint kinase 1 (CHK1), a critical effector kinase in DNA damage response, thus promoting radioresistance.
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USP7 purified from 293T cells transfected with USP7 alone decreased CHK1 poly-ubiquitination by 25% in vitro, and USP7 and ZEB1 co-purified from 293T cells with co-transfection of USP7 and ZEB1 reduced CHK1 poly-ubiquitination by 43% (XREF_FIG).
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USP7 deubiquitinates ANXA1. 6 / 6
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In this regard, we suggest that deubiquitination of ANXA1 by HAUSP is essential for UV induced damage responsive function of ANXA1.
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The result showed that HAUSP could reduce the ANXA1 ubiquitination level more upon UV, possibly due to the increase in HAUSP-ANXA1 binding.
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Collectively, our data suggest that the deubiquitination of ANXA1 is specifically mediated by HAUSP, and HAUSP mediated deubiquitination of ANXA1 may be important for ANXA1 's damage response function in the nucleus upon UV.
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In this regard, our result of immunofluorescence analysis in HAUSP KD HeLa cells, which showed translocation of nuclear ANXA1 to the cytosol (XREF_FIG), may be due to the failure of deubiquitination of ANXA1 mediated by HAUSP.
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These data suggest that deubiquitination of ANXA1 by HAUSP is essential for the UV induced damage response function of ANXA1 in Jurkat cells.
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Deubiquitination of ANXA1 by HAUSP regulates UV induced damage response in HeLa cells.
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USP7 deubiquitinates CLSPN. 5 / 5
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Because extracts from mitotic cells readily support ubiquitylation of Claspin in a betaTrCP dependent fashion, we used such an approach to test whether USP7 directly deubiquitylates Claspin in vitro.
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In contrast, little if any effect on Claspin stability was evident in cells expressing USP7 CI (XREF_FIG), which supports the idea that Claspin is deubiquitylated by USP7.
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68 HAUSP deubiquitinates checkpoint kinase Chk1, 69 its activator Claspin, 70 and checkpoint with forkhead and RING finger domain protein (Chfr).
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In such experiments, USP7 CI interacted more strongly with endogenous Claspin than did WT USP7 (XREF_FIG), which is consistent with a substrate trapping mechanism in which an inability of inactive USP7 to deubiquitylate Claspin would manifest as a prolonged binding and thus a tighter interaction.
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USP7 deubiquitinates PCNA. 5 / 5
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USP7 can deubiquitinate PCNA alongside a related DUB, USP1.
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Kashiwaba et al. have additionally shown that USP7 can deubiquitylate PCNA, but this is not coupled to DNA replication and likely plays a role in DNA repair.
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Surprisingly, USP7 also deubiquitylates PCNA.
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Cell-cycle-synchronization analyses revealed that USP7 suppression increased H2O2 induced PCNA ubiquitination throughout interphase, whereas USP1 suppression specifically increased ubiquitination in S-phase cells.
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USP7 deubiquitinates CHFR. 5 / 5
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Thus, we examined whether USP7 can mediate the deubiquitination of Chfr in vivo.
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These results demonstrate that USP7 preferentially functions in deubiquitination of Chfr, and prevents autoubiquitination mediated degradation of Chfr.The present study has demonstrated that Chfr bind[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Deubiquitination of Chfr, a checkpoint protein, by USP7 and HAUSP regulates its stability and activity.
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Ubiquitin specific protease, USP7 and HAUSP deubiquitinates CHFR and prevents its degradation, resulting in the increased stability [9].
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USP7 deubiquitinates DAXX. 5 / 5
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Furthermore, Hausp de-ubiquitinated Daxx and regulated stability of endogenous Daxx.
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Similar to what has been reported with Mdm2 and p53, Hausp strongly de-ubiquitinated Daxx (XREF_FIG).
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The strong interaction between Daxx and Hausp, and that Daxx is ubiquitinated by Mdm2 and other E3s suggest that Hausp might de-ubiquitinate Daxx.
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Daxx is deubiquitinated by Hausp.
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USP7 deubiquitinates IKBKG. 5 / 5
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Cytoplasmic USP7 binds to and deubiquitinates TRAF6 and IKKgamma, thus terminating TLR mediated NF-kappaB and JNK activation.
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The aforementioned data demonstrated that both HSCARG and USP7 inhibit NEMO polyubiquitination, and suppression of NEMO polyubiquitination by HSCARG is dependent on USP7.
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To determine whether USP7 deubiquitinated NEMO polyubiquitination, we examined and compared the levels of NEMO polyubiquitination in HEK 293T cells with or without ectopic USP7.
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Inhibition of NEMO polyubiquitination by USP7 suggested that USP7 probably inhibited cytokine induced NF-kappaB activation.
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USP7 deubiquitinates RB1. 4 / 4
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HAUSP deubiquitinates Rb in vivo and in vitro, leading to an increased cell population in the G1 phase.
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HAUSP deubiquitinates Rb.
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In addition to stabilization of MDM2 by HAUSP, it might be possible that HAUSP reverses Rb ubiquitination by MDM2 in normal cells but is overwhelmed by abundant MDM2 in the case of tumor tissues or cancer cells.
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USP7 deubiquitinates MYCN. 4 / 4
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HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma.
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The ubiquitin specific peptidase HAUSP (also known as USP7) binds to and deubiquitinates MYCN leading to its stabilization (XREF_FIG).
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HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma
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HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma.
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USP7 deubiquitinates RAD18. 4 / 4
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?Here, we identify the de-ubiquitylating enzyme USP7 as a critical regulator of Rad18 protein levels. Loss of USP7 destabilizes Rad18 and compromises UV-induced PCNA mono-ubiquitylation and Pol 畏 recruitment to stalled replication forks.?
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In response to replication stress, USP7 also deubiquitylates and stabilizes both Rad18 (so that it can monoubiquitylate PCNA) and the TLS polymerase, polymerase eta (POL-eta), and this facilitates the bypass of lesions through the error-prone TLS pathway.
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USP7 deubiquitinates RAD18 which leads to stabilisation and up-regulation of PCNA ubiquitination.
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This is likely concomitant with Pol eta deubiquitination by USP7 and PIAS1 and Rad18 dependent SUMOylation [XREF_BIBR, XREF_BIBR] (XREF_FIG A).
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USP7 deubiquitinates CD274. 4 / 4
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Similarly, treatment of MFC cells with mUSP7-sgRNA-lentivirus or Almac4 also led to similar results which further confirm the results derived from XREF_FIG G and H. All these results indicate that USP7 interacts with PD-L1 and deubiquitinates PD-L1 to promote the stability of PD-L1.
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Results in XREF_FIG E suggest that PD-L1 was strongly ubiquitinated (lane 2, XREF_FIG E) in the presence of MG132 but without HA-USP7, while HA-USP7 abolished PD-L1 ubiquitination (lane3, XREF_FIG E).
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In the current study, we show that USP7 deubiquitinates PD-L1 to cause cancer immune resistance to promote cancer growth.
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Then, to further verify that USP7 can deubiquitinate PD-L1, Flag-PD-L1 was co-transfected with HA-His-Ub in the presence of HA-USP7 or not in HEK293cells.
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USP7 deubiquitinates CRYL1. 4 / 4
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These results demonstrate that USP7 deubiquitinates CRY proteins.
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USP7 deubiquitinates CRY proteins.
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Fbxl3 knockdown in HEK293T/17 cells did not abrogate USP7 dependent stabilizing effect on CRY2 (XREF_FIG), suggesting that USP7 deubiquitinates CRY protein that was ubiquitinated by multiple E3 ligases.
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Given that MAGEL2 interacts with USP7, and that CRY proteins are deubiquitinated and stabilized by USP7, we tested the effect of MAGEL2 and USP7 on the ubiquitination of CRY1.
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Modified USP7 leads to the deubiquitination of REST. 4 / 4
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Moreover, deubiquitination assay demonstrated that expression of Wt-HAUSP but not the Mt-HAUSP attenuated the REST ubiquitination induced by B5 shHAUSP (XREF_FIG), showing that Wt-HAUSP functioned through deubiquitination to stabilize REST and rescued the differentiation phenotype induced by knockdown of endogenous HAUSP.
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Consistently, expression of HAUSP reduced REST poly-ubiquitination (XREF_SUPPLEMENTARY, lanes 2, 1), and overexpression of beta-TrCP increased REST ubiquitination (XREF_SUPPLEMENTARY, lanes 3, 2).
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Ectopic expression of Wt-HAUSP but not the Mt-HAUSP decreased REST ubiquitination and increased REST protein levels (XREF_FIG; XREF_SUPPLEMENTARY).
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Importantly, overexpression of HAUSP with beta-TrCP together abolished the increased REST ubiquitination induced by beta-TrCP overexpression (XREF_SUPPLEMENTARY, lanes 4, 3).
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USP7 deubiquitinates E3_Ub_ligase. 4 / 4
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USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2.
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USP7 deubiquitinates several tumour suppressors (p53, PTEN, FOXO and claspin) and E3 ligases (MDM2, Mule and viral proteins ICP0) and therefore regulates important signalling pathways that are involved in tumorigenesis XREF_BIBR XREF_BIBR.
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Interestingly, USP7 can deubiquitinate both p53 and its negative regulator HDM2, an E3 ubiquitin ligase responsible for polyubiquitination and subsequent degradation of p53.
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XREF_BIBR - XREF_BIBR USP7 deubiquitinates and stabilizes not only p53, but also Mdm2, the primary E3 ubiquitin ligase of p53 XREF_BIBR, XREF_BIBR Given that both p53 and Mdm2 are known regulators of the steady-level of Poleta, we speculated that changes in cellular USP7 levels may also modulate Poleta level.
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USP7 deubiquitinates XPC. 4 / 4
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Inhibition of USP7 increases XPC ubiquitination level, and without USP7, cells have decreased efficiency in repairing UV lesions [XREF_BIBR, XREF_BIBR].
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Other proteins involved in the stabilization of XPC might be the deubiquitylating enzymes OTUD4 and USP7, which were shown to deubiquitylate XPC upon UV induced DNA damage XREF_BIBR XREF_BIBR.
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Specifically, UV induced XPC proteasomal degradation occurs without protection by USP7 which deubiquitinates XPC.
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USP7 deubiquitinates NEK2. 4 / 4
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USP7 interacts with and deubiquitinates NEK2.
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Next we examined whether the increase in NEK2 protein levels was dependent upon the deubiquitinating enzymatic activity of USP7, and found that ectopic expression of USP7 decreased NEK2 ubiquitination.
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We therefore examined whether USP7 deubiquitinated NEK2 and affected its function in PAs, and confirmed a specific interaction between USP7 and NEK2 in transiently transfected HEK293T cells using co-immunoprecipitation.
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Studies have shown that USP7 deubiquitinates NEK2 and affects its stability XREF_BIBR.
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USP7 leads to the deubiquitination of PHF8. 4 / 4
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Specifically, we demonstrated that USP7 promotes deubiquitination and stabilization of PHF8, leading to the upregulation of a group of genes, including cyclin A2, that are critical for cell growth and proliferation.
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For instance, USP7 promotes the deubiquitination and stabilization of PHF8 [13].
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showed that USP7 promotes deubiquitination and stabilization of PHF8 in breast cancer MCF7 cells, accounting for a mechanism underlying PHF8 deregulation.
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Here, we report that PHF8 physically associates with the deubiquitinase USP7.
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USP7 deubiquitinates NLRP3. 3 / 3
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However, it is not clear whether USP7 and USP47 directly contribute to NLRP3 deubiquitination or regulate the process somewhere upstream of NLRP3 inflammasome action [108].
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Conversely, deubiquitination of NLRP3 by USP7 and USP47 positively regulates inflammasome activation and USP47 is significantly downregulated in dopaminergic neurons from idiopathic PD patient post-mortem brain samples [XREF_BIBR, XREF_BIBR].
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Therefore, H 2 O 2 treatment increases the protein level of NLRP3 and pro-caspase-1 due to the induction of USP7 dependent deubiquitination of NLRP3 and/or activation of NOX4/ROS/NF-kappaB signaling that is capable of DNA binding.
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USP7 deubiquitinates ECT2. 3 / 3
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USP7 in turn, deubiquitinates and stabilizes ECT2, resulting in a feedforward regulatory circuit that ultimately sustains the expression of oncogenic protein MDM2.
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Given that ECT2 is an ubiquitinated protein XREF_BIBR, XREF_BIBR and USP7 promotes the stabilization of ECT2, we next asked the question whether USP7 functions to deubiquitinate ECT2.
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Specifically, we uncovered that ECT2 and USP7 form a positive feedback loop, in which ECT2 promotes USP7 intermolecular self association, -deubiquitination and -stabilization, and reciprocally, USP7 deubiquitinates and stabilizes ECT2.
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USP7 deubiquitinates UHRF1. 3 / 3
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Indeed, USP7 mediates deubiquitylation of UHRF1, preventing its proteasomal degradation.
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Both UHRF1 and DNMT1 are deubiquitinated and stabilized by USP7 [XREF_BIBR, XREF_BIBR], while UHRF1 is the negative regulator of DNMT1 [XREF_BIBR].
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USP7 deubiquitinates SUV39H1. 3 / 3
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Collectively, these results indicate that shared physical interactions of USP7 and SUV39H1 with MDM2 are required either for USP7 to deubiquitinate SUV39H1 or for MDM2 to ubiquitinate SUV39H1, both re[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Collectively, these results indicate that shared physical interactions of USP7 and SUV39H1 with MDM2 are required for either for USP7 to deubiquitinate SUV39H1 or for MDM2 to ubiquitinate SUV39H1; both resulting in enhanced SUV39H1 stability.
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In the absence of p53, USP7 deubiquitinates SUV39H1 providing protection from MDM2 ubiquitination and USP7, MDM2 and SUV39H1 form a DNA independent trimeric complex.35Finally, the role of US7 in regulation of epigenetic regulators is evidenced by the interaction of USP7 with LSD1.
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USP7 deubiquitinates MARCHF7. 3 / 3
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It has been proposed that USP7 may reverse self-ubiquitination of the Ub E3 ligase MARCH7, thus stabilizing MARCH7 which has been known to regulate the expression levels of E-cadherin and β-catenin
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Exogenous expression and short interfering RNA depletion experiments demonstrate that MARCH7 can be stabilized by both USP9X and USP7, which deubiquitylate MARCH7 in the cytosol and nucleus, respectively.
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It has been proposed that USP7 may reverse self ubiquitination of the Ub E3 ligase MARCH7, thus stabilizing MARCH7 which has been known to regulate the expression levels of E-cadherin and beta-catenin.
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USP7 deubiquitinates NOX4. 3 / 3
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USP7 inhibited NOX4 ubiquitination for degradation which leads to elevated ROS production.
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In summary, this study showed that USP7 deubiquitinates NOX4 to stabilize it, which leads to elevated ROS production.
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This study showed that USP7 interacted with and deubiquitinated NOX4, and the inhibition of ROS production or administration of NOX4 inhibitor significantly inhibited oeUSP7 induced pro OA effects such as enhanced pyroptosis, elevated ROS level, increased IL-1beta and IL-18 levels, and overexpression of NLRP3, GSDMD-N, active caspase-1, and pro-caspase-1.
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USP7 deubiquitinates AR. 3 / 3
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We showed that USP7 associates with AR in an androgen-dependent manner and mediates AR deubiquitination.
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USP7 deubiquitinates full-length AR, but not AR-V7, in prostate cancer cells, which suggests that the LBD domain of AR may be critical for USP7 recruitment.
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USP7 mediates AR deubiquitination and associates with AR, in an androgen dependent manner, driving the transcription of target genes and promoting prostate cells growth [XREF_BIBR].
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USP7 deubiquitinates TRAF6. 3 / 3
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USP15 negatively regulates NFjB activation by deubiquitinating IjB (Harhaj and Dixit 2011) , while USP7 decreases NFkB signalling by deubiquitinating TRAF6 and IKK (Nanduri et al. 2013 ).
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While in vitro interactions of USP7 NTD with TRAFs 1 to 6, intracellular USP7 binding to TRAFs 4 and 6, and USP7 deubiquitination of TRAF6 have been reported, biological targeting and deubiquitination of the TRAFs by USP7 have generally not been assessed.
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Cytoplasmic USP7 binds to and deubiquitinates TRAF6 and IKKgamma, thus terminating TLR mediated NF-kappaB and JNK activation.
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USP7 deubiquitinates EZH2. 3 / 3
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USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells.
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We report here that the PRC2 complex is physically associated with ubiquitin specific protease USP7 in cancer cells where USP7 acts to deubiquitinate and stabilize EZH2.
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USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells.
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USP7 deubiquitinates FOXO. 3 / 3
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This process may be reversed by the deubiquitination of FOXO proteins mediated by HAUSP and USP7.
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Deubiquitination of Foxo is mediated by the deubiquitinating enzyme USP7.
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Deubiquitination of FOXO requires the deubiquitinating enzyme USP7 and HAUSP (herpesvirus associated ubiquitin specific protease), which interacts with and deubiquitinates FOXO in response to oxidative stress.
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USP7 deubiquitinates CDC25A. 3 / 3
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These data support that BRE upregulation facilitates deubiquitylation of CDC25A in the presence of DNA damage by USP7.
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USP7 also deubiquitinates the cell cycle checkpoint CDC25A upon DNA damage in the BRCA deficient cells and contributes to cell survival despite the loss of BRCA mediated genome integrity.
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Furthermore, in a co-immunoprecipitation assay, we found that HAUSP interacts with and deubiquitinates Cdc25A both exogenously and endogenously.
32860838
USP7 leads to the deubiquitination of ARMC5. 3 / 3
| 3
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Silencing of USP7 enhanced ARMC5 ubiquitination and accelerated cell cycle G1/S, subsequently promoted RCC cell proliferation.
33544460
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Conversely, overexpression of USP7, but not its catalytically mutant, reversed ARMC5 ubiquitination levels.
33544460
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Silencing of USP7 decreased ARMC5 levels, accompanied by increasing ARMC5 polyubiquitination, whereas overexpression of USP7 but not its mutants increased ARMC5 levels and reversed ARMC5 polyubiquitination.
33544460
USP7 deubiquitinates RIPK1. 3 / 3
1 | 2
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Subsequently, USP7 deubiquitinates the receptor interacting protein 1 (RIP1), resulting in positive regulation of TNF-alpha-induced apoptosis.
24392305
ubibrowser
Review
27775833
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USP7 also deubiquitinates RIP1 following activation by the TRIM27 E3 ligase resulting in apoptosis.
29479529
USP7 deubiquitinates CRY1. 3 / 3
1 | 2
ubibrowser
We found that ubiquitin-specific protease 7 (USP7 also known as HAUSP) associates with CRY1 and CRY2 and stabilizes CRYs through deubiquitination.
27123980
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Recombinant Hausp can deubiquitinate Cry1 in vitro (XREF_FIG).
25756610
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We then tested whether USP7 can deubiquitinate CRY1.
32315313
USP7 leads to the deubiquitination of KDM1A. 3 / 3
1 | 2
ubibrowser
Review
29142505
reach
USP7 inhibited LSD1 ubiquitination and stabilized LSD1 in A172 and T98G cells.
27632941
reach
Furthermore, USP7 inhibits LSD1 ubiquitination and stabilizes LSD1in glioma [XREF_BIBR].
30150556
Modified USP7 leads to the deubiquitination of FOXP3. 3 / 3
| 3
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Ectopic expression of USP7 specifically decreased Foxp3 polyubiquitination, resulting in increased Foxp3 expression.
25152867
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Ectopic expression of USP7 specifically decreased Foxp3 polyubiquitination, resulting in increased Foxp3 protein expression.
23973222
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Ectopic expression of USP7 decreased Foxp3 polyubiquitination and increased Foxp3 expression.
23973222
Modified USP7 leads to the deubiquitination of TP53. 3 / 3
| 3
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There also seems to be a delicate balance between these proteins, as a modest reduction of HAUSP levels prevents p53 deubiquitination but complete ablation of HAUSP causes robust p53 stabilization.
20404858
reach
As shown in XREF_FIG, Mdm2 induced the ubiquitination of p53; however, p53 ubiquitination was significantly diminished by coexpression of USP10 or HAUSP.
20096447
reach
The expression of USP7/HAUSP prevents p53 ubiquitination from Mdm2 as a p53-specific E3 ligase and increases the p53 protein stability [25].
| PMC
USP7 deubiquitinates PRC1. 3 / 3
1 | 2
reach
Lastly, USP7 and USP11 deubiquitinate PRC1, a protein found to contribute to cancer stemness [XREF_BIBR - XREF_BIBR].
30831436
reach
In some cancer types, PRC1 can be deubiquitinated by USP7, USP11 and USP26 [XREF_BIBR, XREF_BIBR].
29142505
ubibrowser
Review
29142505
USP7 leads to the deubiquitination of AXIN1. 2 / 2
1 | 1
ubibrowser
USP7 directly interacts with Axin through its TRAF domain, and promotes deubiquitination and stabilization of Axin.
31519875
reach
Ubiquitin carboxyl-terminal hydrolase 7 (USP7), a potent negative regulator of Wnt and beta-catenin signaling, promotes the deubiquitination and stabilization of AXIN by interacting with AXIN through its TRAF domain [XREF_BIBR].
33291655
USP7 deubiquitinates GLI1. 2 / 2
1 | 1
reach
HAUSP Deubiquitinates Gli and Promotes Hh Signaling Activity in Mammalian Systems.
26120032
ubibrowser
Deubiquitination of Ci/Gli by Usp7/HAUSP regulates Hedgehog Signaling
26120032
USP7 deubiquitinates TP53 on lysine. 2 / 2
2 |
biopax:reactome
No evidence text available
biopax:pid
No evidence text available
17268548
USP7 deubiquitinates NEDD4L. 2 / 2
1 | 1
ubibrowser
USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2.
33106424
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USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2.
33106424
USP7 deubiquitinates FBP1. 2 / 2
| 2
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Moreover, we revealed that ubiquitin carboxyl-terminal hydrolase 7 (USP7) binds to and induces the deubiquitination of FBP1, which prevented FBP1 from translocating to the nucleus.
34854226
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Deubiquitination of FBP1 by USP7 blocks FBP1-DNMT1 interaction and decreases the sensitivity of pancreatic cancer cells to PARP inhibitors.
34854226
USP7 deubiquitinates NOTCH1. 2 / 2
| 2
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USP7 deubiquitinated NOTCH1 in vivo and in vitro, whereas knockdown of USP7 increased the ubiquitination of NOTCH1.
30370059
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USP7 deubiquitinates and stabilizes NOTCH1 in T-cell acute lymphoblastic leukemia.
30370059
USP7 deubiquitinates IKK_complex. 2 / 2
| 2
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USP15 negatively regulates NFjB activation by deubiquitinating IjB (Harhaj and Dixit 2011) , while USP7 decreases NFkB signalling by deubiquitinating TRAF6 and IKK (Nanduri et al. 2013 ).
30244323
reach
USP15 negatively regulates NFκB activation by deubiquitinating IκB (Harhaj and Dixit 2011), while USP7 decreases NFkB signalling by deubiquitinating TRAF6 and IKK (Nanduri et al. 2013).
30244323
USP7 deubiquitinates USP7. 2 / 2
| 2
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In addition, utilizing the UbiTest analysis we demonstrate that inhibition of USP7 increases polyubiquitination of Foxp3, Tip60 and USP7.
29236775
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However, HAUSP also deubiquitinates MDM2 and reduction of HAUSP levels, either by RNA interference or by gene deletion, produces a complex phenotype [XREF_BIBR - XREF_BIBR].
24143256
USP7 deubiquitinates Wnt. 2 / 2
| 2
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31 HAUSP in complex with RNF220 deubiquitinates beta-catenin-enhancing canonical Wnt signaling.
29967688
reach
Collectively, we concluded that the USP7 mediated beta-catenin deubiquitination and Wnt activation are specific to CRCs carrying APC mutations and are p53 independent.
29045831
USP7 leads to the deubiquitination of UBE2E1. 2 / 2
1 | 1
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We show that USP7 attenuates UbE2E1 mediated ubiquitination, an effect that requires the N-terminal ASTS sequence of UbE2E1 as well as the catalytic activity of USP7.
23603909
ubibrowser
UbE2E1/UbcH6 is an E2 ubiquitin-conjugating enzyme that is regulated by USP7.
28073915
USP7 deubiquitinates Histone_H3. 2 / 2
| 2
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USP7 stabilizes several other histone associated proteins including acetyltransferase TIP60, demethylase PHF8, methyltransferase MLL5, lysine specific demethylase 1 (LSD1 and KDM1), and directly deubiquitinates histone H3.
30807924
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Our results thus suggest that histone H3 deubiquitylation by Usp7 is an important step in the maintenance of DNA methylation.
28246399
USP7 leads to the deubiquitination of Cyclin on A2. 2 / 2
| 2
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The exosomal circ-DB internalized by HCC cells can be used as a molecular sponge to absorb miR-34a endogenously, thereby deinhibiting the downstream target USP7, which inhibits the ubiquitination of cyclin A2 protein to maintain its stability.
33869059
reach
USP7 mediates the deubiquitination of cyclin A2 in HCC.
30546088
USP7 leads to the deubiquitination of BMI1. 2 / 2
1 | 1
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Also, a recent study suggested that USP7 attenuates the ubiquitination of BMI1, its homologue Mel-18, and RING1A, which are components of the PRC1 complex [15].
20800574
ubibrowser
Review
27919796
USP7 leads to the deubiquitination of tat. 2 / 2
| 2
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USP7 has also been shown to promote HIV-1 infection by deubiquitylating and stabilizing the HIV-1 Tat protein 73.
30367141
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Finally, besides its role in infections mediated by Herpesviruses, USP7 also promotes adenoviral replication via interaction with viral multifunctional protein E1B-55K and enhances HIV viral production by deubiquitinating its Tat protein.
30807924
USP7 leads to the deubiquitination of PML. 2 / 2
1 | 1
ubibrowser
Review
27775833
reach
Here we showed that USP7 can also function independently from its deubiquitylating activity to negatively regulate the levels of PML proteins and the formation of PML-NBs, by inducing the polyubiquitylation of PML.
21305000
USP7 deubiquitinates ubiquitinated TP53. 2 / 2
| 2
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HAUSP specifically deubiquitinates the ubiquitinated p53 protein both in vitro and in vivo, and the expression of HAUSP was found to stabilize p53 in vivo and to promote p53 dependent cell growth arre[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
12507430
reach
Single- or double ubiquitinated p53 are deubiquitinated by a protein called HAUSP XREF_BIBR.
25504419
USP7 deubiquitinates TRIM27. 2 / 2
1 | 1
ubibrowser
Our findings suggest that USP7 acts as a negative regulator in antiviral signaling by stabilizing TRIM27 and promoting the degradation of TBK1.
29688809
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First, USP7 deubiquitinates TRIM27 to prevent its own auto-degradation and thus stabilizes the complex.
28626083
USP7 deubiquitinates washc1. 2 / 2
| 2
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Taken together, these results suggest that USP7 limits overproduction of endosomal F-actin by WASH through its ability to deubiquitinate WASH and that precise endosomal F-actin levels are critical for[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Taken together, these results suggest that USP7 limits overproduction of endosomal F-actin by WASH through its ability to deubiquitinate WASH (XREF_FIG) and that precise endosomal F-actin levels are critical for proper endosomal protein recycling.
26365382
USP7 deubiquitinates EDNRA. 2 / 2
| 2
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Pol eta is also deubiquitinated by USP7, leading to the recruitment of PCNA to stalled replication forks and PCNA 's ubiquitination by Rad 6 and Rad18 [XREF_BIBR].
30897496
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This is likely concomitant with Pol eta deubiquitination by USP7 and PIAS1 and Rad18 dependent SUMOylation [XREF_BIBR, XREF_BIBR] (XREF_FIG A).
28067843
USP7 deubiquitinates SVIL. 2 / 2
| 1 1
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USP7 binds directly to the supervillin N terminus and can deubiquitinate and stabilize supervillin.
23382381
trips
USP7 binds directly to the supervillin N terminus and can deubiquitinate and stabilize supervillin.
23382381
USP7 deubiquitinates CRY2. 2 / 2
1 | 1
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Here, we demonstrated that, even in the absence of any DNA damage inducible stimuli, not only CRY1 but also CRY2 binds to USP7 and is deubiquitinated by USP7 (Figs XREF_FIG and XREF_FIG).
27123980
ubibrowser
We found that ubiquitin-specific protease 7 (USP7 also known as HAUSP) associates with CRY1 and CRY2 and stabilizes CRYs through deubiquitination.
27123980
USP7 deubiquitinates RELA. 2 / 2
1 | 1
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However, USP7 deubiquitinates the NF-kappaB p65 subunit, which is an important regulator of inflammation, but the USP7 inhibitor targets all the substrates of USP7, not only p65.
33138315
ubibrowser
Review
25121098
USP7 leads to the deubiquitination of FOXO4. 2 / 2
1 | 1
ubibrowser
Review
27775833
reach
USP7 negatively regulates FOXO by antagonizing FOXO4 monoubiquitylation and activity without affecting protein stability.
26154057
USP7 leads to the deubiquitination of NFE2L1. 1 / 1
| 1
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In contrast, knockdown or pharmacologic inhibition of USP7 dramatically increased ubiquitination of TCF11 and Nrf1a, and reduction of their steady state levels.
33933455
USP7 deubiquitinates POLH. 1 / 1
1 |
ubibrowser
USP7 directly serves as a specific DUB for Poleta
25435364
USP7 deubiquitinates RNF168. 1 / 1
1 |
ubibrowser
Review
28031783
Modified USP7 leads to the deubiquitination of CTNNB1. 1 / 1
| 1
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Expression of WT USP7 robustly suppressed beta-catenin ubiquitination, as demonstrated by mobility shift, while the C223A mutant expression failed to execute its function (XREF_FIG H and XREF_SUPPLEMENTARY G).
29045831
USP7 deubiquitinates FUS. 1 / 1
| 1
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In response to replication stress, USP7 also deubiquitylates and stabilizes both Rad18 (so that it can monoubiquitylate PCNA) and the TLS polymerase, polymerase eta (POL-eta), and this facilitates the bypass of lesions through the error-prone TLS pathway.
29357069
USP7 deubiquitinates MAFA. 1 / 1
| 1
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Stability of MAF proteins in MM is further regulated by the deubiquitinases ubiquitin specific peptidase 5 (USP5), which prevents degradation of c-MAF and MAFB [XREF_BIBR], and USP7, which can deubiquitinate c-MAF, MAFA and MAFB [XREF_BIBR].
33494394
Modified USP7 leads to the deubiquitination of DNMT1. 1 / 1
| 1
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Second, DNMT1 ubiquitination was increased in the HAUSP knockout cells (XREF_FIG), whereas overexpression of HAUSP led to deubiquitination of DNMT1 (XREF_FIG).
21045206
USP7 deubiquitinates IRS2. 1 / 1
1 |
ubibrowser
Review
27775833
USP7 leads to the deubiquitination of mutated DNMT1. 1 / 1
| 1
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Experimental controls further showed that (i) a HAUSP C223S (active site) mutant could not remove ubiquitin moieties from DNMT1 (XREF_FIG), and (ii) overexpressed HAUSP failed to deubiquitinate a DNMT1 mutant lacking the HAUSP interaction domain (DNMT1Delta) (XREF_SUPPLEMENTARY).
21045206
USP7 leads to the deubiquitination of RING1. 1 / 1
| 1
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His ubiquitin pull-down analysis showed that HSCARG and USP7 inhibited RING1 ubiquitination in a synergy manner.
24711370
USP7 leads to the deubiquitination of ARF4. 1 / 1
| 1
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USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4.
34556124
USP7 deubiquitinates HIF1. 1 / 1
| 1
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The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin.
34740372
USP7 deubiquitinates FOXP3. 1 / 1
| 1
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56 In other words, USP7 deubiquitinates Foxp3, increasing Foxp3 protein levels and subsequently up-regulating Treg cells.A knockdown of USP7 expression in the Treg cells leads to a decrease in the Foxp3 protein levels reducing the suppression of the Treg-cell in vitro and vivo.45 USP7 inhibitors can affect the tumour growth limitation in immunocompetent mice and may have a key role in future cancer immunotherapies.56USP7 has also been implicated in regulation of the inflammasome.
| PMC
USP7 deubiquitinates FOXO3. 1 / 1
1 |
ubibrowser
USP7 deubiquitinates checkpoint with forkhead and RING finger domains protein (Chfr), which in turn ubiquitinates histone deacetylase 1 (HDAC1), leading to upregulation of p21Cip1/Waf1?and induction of G1 arrest
25121098
USP7 deubiquitinates CREB3. 1 / 1
| 1
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Similarly, USP7 deubiquitination of FOXO4 's monoubiquitinated, transcriptionally active form excludes it from the nucleus, eliminating its activity [XREF_BIBR].
30897496
USP7 deubiquitinates ALKBH3. 1 / 1
| 1
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Instead, it seemed to act as a scaffold protein, recruiting two further DUBs, USP7 and USP9x, which then de-ubiquitylated ALKBH3.
26588485
USP7 deubiquitinates PCGF2. 1 / 1
| 1
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Nevertheless, MEL18 and BMI were deubiquitylated by USP7 and USP11, two chromatin bound components of polycomb and repressive complex 1 complex components that influence the transcriptional regulation of p16INK4a [XREF_BIBR].
25972356
Modified USP7 leads to the deubiquitination of CRY1. 1 / 1
| 1
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CRY1 is ubiquitinated in this assay (XREF_FIG, CRY1 ub smear in lane 2), and co-expression of USP7 reduced CRY1 ubiquitination (ubiquitin smear in lane 3 compared to lane 2).
32315313
USP7 deubiquitinates ubiquitinated HIF1A. 1 / 1
| 1
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In vitro deubiquitination assays using purified polyubiquitinated HIF-1alpha and Flag-HAUSP (wild-type versus K443R mutant) showed that the wild-type HAUSP, but not the K443R mutant, significantly deubiquitinated the polyubiquitinated HIF-1alpha species (XREF_FIG).
27934968
USP7 deubiquitinates ubiquitinated HSD17B8. 1 / 1
| 1
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USP7 also deubiquitinates autoubiquitinated RING2 ligase of the polycomb complex and RING2 that has been marked for degradation by the E6AP ligase.
23845989
USP7 deubiquitinates TRRAP. 1 / 1
| 1
trips
HAUSP regulates c-MYC expression via de-ubiquitination of TRRAP.
25925205
Modified USP7 leads to the deubiquitination of SPRTN. 1 / 1
| 1
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Furthermore, deubiquitylation of SPRTN induced by overexpression of USP7 WT, but not of catalytically inactive USP7 CS, leads to reduced formation of autocatalytic SPRTN fragments.
33348378
USP7 deubiquitinates TP53BP1. 1 / 1
1 |
ubibrowser
53BP1 depletion induces mitotic defects such as disorientation of spindle poles attributed to extra centrosomes or mispositioning of centrosomes, leading to phenotypes similar to those in USP7-deficient cells.
28930533
Modified USP7 leads to the deubiquitination of TBK1. 1 / 1
| 1
reach
Overexpression of USP7 promoted the ubiquitination and degradation of TBK1 through promoting the stability of TRIM27.
29688809
USP7 deubiquitinates H2BC10. 1 / 1
1 |
ubibrowser
Review
27775833
USP7 deubiquitinates MYC. 1 / 1
1 |
ubibrowser
Most importantly, we are able to demonstrate that USP7 deubiquitinates and thereby stabilizes c-Myc and that this function is required to maintain neural stem cell fate.
29899379
USP7 leads to the deubiquitination of ICP0. 1 / 1
| 1
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47 Similarly, HAUSP blocks ICP0 autoubiquitination 48 and enhances ICP0 protein stability.
22945642
USP7 deubiquitinates RAE1. 1 / 1
| 1
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USP7, which co-IPs with USP11 and can co-IP USP11, RAE1, PAM and SPRYD3 (XREF_SUPPLEMENTARY), efficiently deubiquitinated SPRYD3, whilst RAE1 is only weakly deubiquitinated by USP7 (XREF_FIG).
29293652
USP7 deubiquitinates FOXO1. 1 / 1
1 |
ubibrowser
Review
27775833
USP7 deubiquitinates YAP1. 1 / 1
1 |
ubibrowser
Furthermore, the mammalian homolog of Usp7, HAUSP plays a conserved role in regulating Hippo pathway by modulating Yap ubiquitination and degradation.
30679505
USP7 deubiquitinates DNMT3B. 1 / 1
| 1
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FA decreased the ubiquitination of DNMT1 (p = 0.0753), DNMT3A (p = 0.0008) and DNMT3B (p < 0.0001) by decreasing UHRF1 (p < 0.0001) and USP7 (p < 0.0001).
31060424
Modified USP7 leads to the deubiquitination of GMPS. 1 / 1
| 1
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Of note, USP7 overexpression leads to GMPS deubiquitylation and nuclear retention.
24507714
USP7 deubiquitinates NFKB1. 1 / 1
1 |
ubibrowser
Review
27775833
Modified USP7 leads to the deubiquitination of NCL. 1 / 1
| 1
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Overexpression of wild-type HAUSP, but not a catalytic mutant (C223S) decreased nucleolin ubiquitination (XREF_FIG, lane 3).
26238070
USP7 deubiquitinates RNF220. 1 / 1
| 1
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Specifically, USP7 binds the N-terminus of β-catenin when the APC losses CID confirming the essential role of USP7 in the activation of Wnt signalling and cell survival in colorectal cancers.13 Ma et al showed that the USP7/RNF220 complex activates the Wnt pathway while knockdown of USP7 using a small interfering RNA (siRNA) strategy, reduces the expression of Wnt.18 Conversely, a recent study proposed that USP7 deubiquitinates β-catenin and RNF220 independently and works as a tumour-specific condition when APC is mutated.
| PMC
USP7 leads to the deubiquitination of NCL. 1 / 1
| 1
reach
Therefore, we examined the pattern of polyubiquitination and deubiquitination of nucleolin following HAUSP overexpression (XREF_FIG).
26238070
USP7 deubiquitinates SIRT7. 1 / 1
1 |
ubibrowser
Ubiquitin-specific peptidase 7 (USP7)-mediated deubiquitination of the histone deacetylase SIRT7 regulates gluconeogenesis
28655758
USP7 deubiquitinates PTEN ubiquitinated on K13 on K289. 1 / 1
1 |
biopax:reactome
No evidence text available
USP7 deubiquitinates RARA. 1 / 1
1 |
ubibrowser
overexpression or depletion of USP37 caused an increase or decrease of PLZF/RARA protein half-life, correlating with down- or upregulation of PLZF/RARA poly-ubiquitination, respectively. By PLZF/RARA-transduced primary mouse hematopoietic progenitor cells, we demonstrated that Usp37 knockdown alleviated PLZF/RARA-mediated target gene suppression and cell transformation potential
23208507
USP7 deubiquitinates HLTF. 1 / 1
1 |
ubibrowser
Review
27775833
USP7 deubiquitinates IRS1. 1 / 1
1 |
ubibrowser
Review
27775833
USP7 deubiquitinates FOXO4 on lysine. 1 / 1
1 |
biopax:pid
No evidence text available
16964248
USP7 deubiquitinates HSD17B8. 1 / 1
| 1
reach
USP7 also deubiquitinates autoubiquitinated RING2 ligase of the polycomb complex and RING2 that has been marked for degradation by the E6AP ligase.
23845989
USP7 deubiquitinates MAF. 1 / 1
| 1
reach
Stability of MAF proteins in MM is further regulated by the deubiquitinases ubiquitin specific peptidase 5 (USP5), which prevents degradation of c-MAF and MAFB [XREF_BIBR], and USP7, which can deubiquitinate c-MAF, MAFA and MAFB [XREF_BIBR].
33494394
USP7 deubiquitinates transcriptional activator. 1 / 1
| 1
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39 USP7 also deubiquitinates RNA transcriptional activator associated ubiquitin ligase and prevents it from self-ubiquitination-mediated degradation.
24832601
USP7 deubiquitinates UVSSA. 1 / 1
1 |
ubibrowser
The central region of UVSSA, which contains the tumor necrosis factor receptor-associated factor (TRAF)-binding motif, is required for the interaction with the N-terminal TRAF domain of USP7. Here, we showed that UVSSA is mono-ubiquitinated in?vitro and identified a lysine residue (Lys414?) in UVSSA as the target of ubiquitination. The deubiquitination activity of USP7 was inhibited by the ubiquitin-conjugating enzyme UbcH6. Lys414?was also modified by poly-ubiquitin chains in?vivo.?
29323787
USP7 deubiquitinates AURKA. 1 / 1
1 |
ubibrowser
Review
27775833
USP7 deubiquitinates MAFB. 1 / 1
| 1
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Stability of MAF proteins in MM is further regulated by the deubiquitinases ubiquitin specific peptidase 5 (USP5), which prevents degradation of c-MAF and MAFB [XREF_BIBR], and USP7, which can deubiquitinate c-MAF, MAFA and MAFB [XREF_BIBR].
33494394
Modified USP7 leads to the deubiquitination of FOXP3. 1 / 1
| 1
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As expected, USP44 or USP7 expression alone reduced ubiquitination of FOXP3, while co-over-expression of both USP44 and USP7 almost completely eliminated FOXP3 polyubiquitination, suggesting a synergistic role of these two DUBs (Fig XREF_FIG C).
32644293
USP7 deubiquitinates SPRYD3. 1 / 1
| 1
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USP7, which co-IPs with USP11 and can co-IP USP11, RAE1, PAM and SPRYD3 (XREF_SUPPLEMENTARY), efficiently deubiquitinated SPRYD3, whilst RAE1 is only weakly deubiquitinated by USP7 (XREF_FIG).
29293652
USP7 deubiquitinates TRIP12. 1 / 1
1 |
ubibrowser
Ubiquitin-specific protease 7 accelerates p14(ARF) degradation by deubiquitinating thyroid hormone receptor-interacting protein 12 and promotes hepatocellular carcinoma progression
25557975
USP7 deubiquitinates KMT2E. 1 / 1
| 1
reach
To determine whether USP7 deubiquitinates MLL5 protein, we used a lentiviral based shRNA approach to eliminate USP7 expression in HeLa cells, and examined the effects on MLL5 protein.
26678539
USP7 deubiquitinates PTEN ubiquitinated on K289 on K13. 1 / 1
1 |
biopax:reactome
No evidence text available
USP7 deubiquitinates SIRT1. 1 / 1
| 1
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USP7 Deubiquitinates and Stabilizes SIRT1.
31502386
USP7 deubiquitinates PPARG. 1 / 1
1 |
ubibrowser
Review
27775833
USP7 deubiquitinates RELB. 1 / 1
| 1
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In contrast, both WT USP7 and USP7DeltaUbl2 were able to deubiquitinate RelB, demonstrating that Ubl2 is dispensable for USP7 interaction with and deubiquitination of RelB (XREF_FIG B).
32587091
USP7 leads to the deubiquitination of Histone. 1 / 1
| 1
reach
44 HAUSP promotes deubiquitination and stabilization of the histone demethylase PHF8, leading to the upregulation of a group of genes, including cyclin A2, which are critical for cell growth and proliferation in breast cancer.
29967688
USP7 leads to the deubiquitination of AXIN. 1 / 1
| 1
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Deubiquitination of Axin mediated by USP7 prevents Axin from degrading and providing stability.
32486158
USP7 deubiquitinates DNMT3A. 1 / 1
| 1
reach
FA decreased the ubiquitination of DNMT1 (p = 0.0753), DNMT3A (p = 0.0008) and DNMT3B (p < 0.0001) by decreasing UHRF1 (p < 0.0001) and USP7 (p < 0.0001).
31060424
USP7 deubiquitinates BUB3. 1 / 1
1 |
ubibrowser
Review
27775833
USP7 deubiquitinates KDM6A. 1 / 1
| 1
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USP7 deubiquitinated KDM6A to increase its expression.
34645609
USP7 deubiquitinates HUWE1. 1 / 1
| 1
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In addition to its substrates, HUWE1 also mediates selfubiquitination; this is counteracted by Ser18 containing isoform of ubiquitin-specific-processing protease 7 (USP7S) that de-ubiquitinates HUWE1 and prevents its subsequent degradation XREF_BIBR - XREF_BIBR.
29118367
USP7 leads to the deubiquitination of UHRF1-K659E. 1 / 1
| 1
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In contrast, USP7 can not reduce the autoubiquitination of the UHRF1 K659E mutant.
26299963
Mutated USP7 deubiquitinates CHEK1. 1 / 1
| 1
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Importantly, wild type, but not catalytic mutant USP7 can deubiquitinate Chk1 in vivo and in vitro, confirming that USP7 directly regulates Chk1 protein levels.
25483066
USP7 deubiquitinates POU5F1. 1 / 1
1 |
ubibrowser
Review
27919796
Modified USP7 leads to the deubiquitination of IKBKG. 1 / 1
| 1
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As expected, the results of ubiquitin conjugation assays showed that overexpression of USP7 strongly inhibited polyubiquitination of NEMO (XREF_FIG, XREF_SUPPLEMENTARY).
24832601
USP7 deubiquitinates ubiquitinated RNF2. 1 / 1
| 1
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Taken together, these results suggest that USP7 might regulate the ubiquitinated state and therefore the activity of multiple PcG proteins.Since binding of RING1B to USP7 is partially dependent on its[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Other Statements

psp cbn pc bel_lc signor biogrid tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi minerva creeds ubibrowser acsn | geneways tees gnbr semrep isi trips rlimsp medscan eidos sparser reach
USP7 affects TP53
1 | 8 2 138
USP7 activates TP53.
1 | 4 2 78
USP7 activates TP53. 10 / 94
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Correspondingly, it is highly possible that the regulation of USP7 mediated p53 function by TSPY1 is an important molecular mechanism underlying its function in human spermatogenesis.
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The fact that STIP is involved in two different ternary complexes raises the possibility that this interaction may facilitate the USP7 mediated the stabilization of Mdm2 and p53.
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Chemical inhibition of USP7 and Wip1 impairs the viability of TP53 wild-type Ewing sarcoma cells.
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The findings suggest an additional mechanism underlying the regulation of spermatogonial p53 function, indicating the significance of TSPY1 in germline homeostasis maintenance and the potential of TSPY1 in regulating human spermatogonial proliferation via the USP7 mediated p53 signaling pathway.
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Overexpression of USP7 induces p53 activation, leading to growth suppression and apoptosis.
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Hdm2 is preferentially targeted by USP7 over p53 under normal unstressed conditions; however, USP7 targets p53 in response to DNA damage.
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The herpesvirus associated ubiquitin specific protease (also named as USP7) can be activated by ATM to stabilize p53 response to DNA damage.
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There also seems to be a delicate balance between these proteins, as a modest reduction of HAUSP levels prevents p53 deubiquitination but complete ablation of HAUSP causes robust p53 stabilization.
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In contrast, a more modest reduction in HAUSP causes a decrease in both MDM2 and p53 stability, suggesting that, under these conditions, sufficient MDM2 remains to degrade p53.
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HAUSP strongly stabilizes p53 even in the presence of excess Mdm2, and also induces p53 dependent cell growth repression and apoptosis.
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Modified USP7 activates TP53. 2 / 2
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The expression of USP7/HAUSP prevents p53 ubiquitination from Mdm2 as a p53-specific E3 ligase and increases the p53 protein stability [25].
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Collectively, the data suggest that overexpression of USP7 up-regulates steady-levels of Poleta independent of p53 and suggested that Poleta, like p53, could be a substrate of USP7.
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USP7 bound to WRAP53 activates TP53. 1 / 1
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XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In this study, we report a new molecular process in which WDR79 interacts with USP7 to modulate the stability of Mdm2 and p53, which promotes the proliferation of NSCLC cells.
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USP7 inhibits TP53.
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USP7 inhibits TP53. 10 / 40
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For example, expression of EBNA1 but not a USP7 binding mutant of EBNA1 was shown to reduce the accumulation of p53 in response to DNA damage in U2OS cells [XREF_BIBR].
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Our results support a new role for vIRF1 through deregulation of the deubiquitinating enzyme USP7 to inhibit p53 mediated antiviral responses.
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Notably, selective dual inhibitors of USP7 and USP47 have been synthesized and induced accumulation of p53 and apoptosis in human cancer cell lines [XREF_BIBR].
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As p53 is activated by genotoxic stress and has a key role in genotoxic stress induced cell death, we reasoned that pharmacological inhibition of USP7 activity would potentiate p53 activity and result in increased chemosensitivity.
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The inhibition of USP7 with HBX 41,108, a DUB to Hdm2 has shown to induce p53 dependent apoptosis with an IC in sub-micro-molar concentrations.
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More recently, it has been shown that a small molecule inhibitor of HAUSP, HBX41108, stabilizes p53 and induces p53 dependent apoptosis in cancer cell lines that retain wild-type p53 [XREF_BIBR].
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Hence, inhibition of Usp7 is thought to inactivate Mdm2 and thereby activate p53, resulting in inhibition of cell cycle progression and tumor cell apoptosis.
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On the other hand, by ubiquitinating itself, MDM2 targets itself for destruction and promotes the p53 tumor suppressor pathway, a process that can be antagonized by the deubiquitinase herpesvirus associated ubiquitin specific protease (HAUSP).
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Typically , USP7 could stabilize MDM2 by deubiquitination and subsequently promotes the degradation of p53 , causing the inhibition of apoptosis in cancer cells ( Bhattacharya et al. 2018 ) .
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Inhibition of USP7 is expected to increase p53 levels , leading to anti-tumour activity [ 79 , 80 ] .
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Modified USP7 inhibits TP53. 2 / 2
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Expression of USP7, the target protein of EBNA1 and ICP0, however, effectively promotes increased levels of p53 by antagonizing proteasomal degradation of p53 through deubiquitination.
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Expression of USP7, the target protein of EBNA1 and ICP0, however, effectively promotes increased levels of p53 by antagonizing proteasomal degradation of p53 through deubiquitination (Li et al., 2004).
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USP7 bound to TP53 inhibits TP53. 1 / 1
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Furthermore, EBNA-1-USP7 interaction prevents the binding of USP7 to p53 and thereby diminishes p53 stabilization.
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USP7 decreases the amount of TP53.
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USP7 decreases the amount of TP53. 10 / 17
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USP7 (ubiquitin specific protease 7), which deubiquitinates HDM2, can lead to increased levels of HDM2 and decreased levels of p53.
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Although a partial reduction in HAUSP can increase p53 levels, drastic reduction can have the opposite effect [17].
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HCT116 USP7 -/- cells grow extremely slowly because USP7 knockout leads to constitutively high level of p53 and p21.
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However depletion of HAUSP in cells does not decrease p53 levels as predicted, but rather increases p53 levels, apparently due to HAUSP 's ability to bind and deubiquitinate Mdm2.
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There is precedent for this possibility as, under some circumstances, USP7 can negatively regulate p53 levels by stabilizing the Mdm2 E3 ligase XREF_BIBR, XREF_BIBR.
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Inhibition of USP7 is expected to increase p53 levels, leading to anti-tumour activity [79], [80].
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USP7/HAUSP can elongate p53; however, depletion of USP7/HAUSP also induces upregulation of p53 protein expression [27].
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However, double silencing of USP7 and FAM188B restored the p53 level.
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Similar to RNAi-mediated USP7 silencing in cancer cells, HBX41,108 treatments stabilized p53, activated transcription of a p53 target gene without inducing genotoxic stress, and inhibited cancer cell growth [119] .
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On the other side, the ubiquitinated TP53 could be reversed and stabilized by USP7 and USP10, to keep the amount of TP53 in check.
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USP7 decreases the amount of ubiquitinated TP53. 1 / 1
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Conversely, FAM188B downregulation increased unbound USP7 and this free USP7 may decrease the level of ubiquitinated p53.
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USP7 increases the amount of TP53.
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USP7 increases the amount of TP53. 10 / 10
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By regulating p53 levels through their deubiquitinating activities, USP7 and USP2a may contribute to cancer pathogenesis and therapeutic strategies that target these p53 specific DUBs may become important as cancer treatments [XREF_BIBR].
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While USP7 can directly regulate p53 levels, these levels can also be regulated by the DUB USP2a.
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To balance this action, HAUSP and USP7, an ubiquitin hydrolase, in turn regulates MDM2 activity and therefore P53, while the deubiquitinating enzyme USP7 works to augment P53 levels through inhibition of its degradation [XREF_BIBR].
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Initially, USP7 was believed to primarily deubiquitinate p53, increasing the level of p53 [17] .
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By simulating TSPY1 function in Tspy1 deficient spermatogonia derived from mouse testes, we found that TSPY1 could promote spermatogonial proliferation by decreasing the Usp7 modulated p53 level.
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Both, the DUB HAUSP (herpesvirus associated ubiquitin specific protease) and USP10 (ubiquitin specific protease 10), targeting poly-ubiquitinated p53, have been shown to restore p53 levels even when Hdm2 is overexpressed.
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However, knockout of USP7 in cells does not decrease p53 levels as predicted, but rather stabilizes p53 [XREF_BIBR].
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As shown in XREF_FIG, knockdown of USP7 reduced the levels of Mdm2 and p53, a result consistent with that of a previous study.
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However depletion of HAUSP in cells does not decrease p53 levels as predicted, but rather increases p53 levels, apparently due to HAUSP 's ability to bind and deubiquitinate Mdm2.
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Silencing of USP7 decreased the p53 level and increased ubiquitinated-p53.
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Modified USP7 increases the amount of TP53. 4 / 4
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In addition, USP7 overexpression significantly increased endogenous Mdm2 and p53 levels, but had no effect on STIP levels (XREF_SUPPLEMENTARY).
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Expression of USP7, the target protein of EBNA1 and ICP0, however, effectively promotes increased levels of p53 by antagonizing proteasomal degradation of p53 through deubiquitination (Li et al., 2004).
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As shown by the Gu group, partial reduction of USP7 levels in several human cell lines promotes decreased levels of both MDM2 and p53, yet total abolition of USP7 stabilizes p53 levels by decreasing MDM2 [117, 118].
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Expression of USP7, the target protein of EBNA1 and ICP0, however, effectively promotes increased levels of p53 by antagonizing proteasomal degradation of p53 through deubiquitination.
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USP7 affects MDM2
1 | 6 58
USP7 activates MDM2.
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USP7 activates MDM2. 10 / 48
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The stability of p53 and its ubiquitin E3 ligases HDM2 and HDMX is modulated by USP7, the de-ubiquitinase of a number of protein targets linked to tumorigenesis [19,23,27] including phosphatase and te[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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The results also demonstrated that USP7 can upregulate MDM2 , and inhibit the expression of p53 .
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HAUSP, a nuclear ubiquitin specific protease, targets p53 and Mdm2 as substrates and, in concert with Mdm2, plays a dynamic role in p53 functionality.
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The stabilized USP7 / HAUSP can enhance Mdm2 and decrease p53 protein expression .
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Another contrasting possibility is that HAUSP can target both p53 and MDM2 for deubiquitylation and thus may play a dynamic role in the p53-MDM2 pathway [XREF_BIBR].
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From a functional perspective, we speculate that, WDR79, a scaffold protein with multiple WD-repeat domains, may form a platform to actively recruit or tether USP7 and its targets Mdm2 and/or p53 from the nucleoplasm, which facilitates the USP7 mediated stabilization of Mdm2 and p53.
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USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy.
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In unstressed cells, SUV39H1 is deubiquitinated and protected from MDM2 mediated degradation by HAUSP, promoting the repression of p53 responsive gene transcription.
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Our study suggests that USP7 up-regulates MDM2 , which facilitates FoxO4 ubiquitinated degradation , and subsequently increases the expression of CyclinD1 to mediate PDGF-induced PASMCs proliferation .
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Supporting evidence suggests that an inhibitor of USP7 would act to abrogate the action of Hdm2, and thereby elevate levels of the p53 protein, with associated therapeutic benefits in cancer and potentially other diseases.
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USP7 bound to WRAP53 activates MDM2. 1 / 1
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XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR In this study, we report a new molecular process in which WDR79 interacts with USP7 to modulate the stability of Mdm2 and p53, which promotes the proliferation of NSCLC cells.
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USP7 bound to MDM2 activates MDM2. 1 / 1
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Daxx promotes the binding of MDM2 to HAUSP and thus increases MDM2 stability.
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USP7 inhibits MDM2.
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USP7 inhibits MDM2. 9 / 11
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Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.
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USP7 also negatively regulates the stability of MDM2.
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As USP7 participates in regulating the P53-murine double minute-2 (MDM2) axis XREF_BIBR, abrogation of USP7 is considered to inactivate MDM2 and subsequently reactivate P53, leading to cell cycle arrest and apoptosis XREF_BIBR.
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Interestingly, severe ablation of USP7 expression diminished Mdm2 but increased Poleta (XREF_FIG).
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XREF_BIBR HAUSP antagonizes the action of MDM2 on P53.
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In fact, a genetic knockout of USP7 caused depletion of MDM2 and, despite the aforementioned rescue effect of USP7 on p53, effectively stabilized p53.
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25 USP7 deficiency in mouse embryonic fibroblasts (MEFs) greatly reduces the half-life of MDM2 and activates p53.
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The role of USP7 in promoting degradation of HDM2 resulting in increased levels of p53 and p21 is documented in multiple models (Chauhan et al., 2012; Kon et al., 2010) .
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Loss of HAUSP mediated deubiquitination contributes to DNA damage induced destabilization of Hdmx and Hdm2.
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Modified USP7 inhibits MDM2. 1 / 1
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Overexpression of USP7 partially, but significantly attenuated ursolic acid induced cell death as well as downregulation of MDM2, UHRF1 and DNMT1.
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USP7 decreases the amount of MDM2.
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USP7 decreases the amount of MDM2. 3 / 7
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Indeed, downregulation of USP10 did not affect Mdm2 levels in p53 deficient cells (XREF_FIG and XREF_SUPPLEMENTARY), while downregulation of HAUSP still decreased Mdm2 levels in p53 deficient cells.
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UbV.7.2 inhibited USP7 in cancer cells, and consequently, caused dramatic reductions of MDM2 levels and induction of apoptosis, in synergy with cisplatin, suggesting that UbVs could be used as enhancers of chemotherapeutic drugs.
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UbV.7.2 inhibited USP7 in cancer cells, and consequently, caused dramatic reductions of MDM2 levels and induction of apoptosis, in synergy with cisplatin, suggesting that UbVs could be used as enhancers of chemotherapeutic drugs (W. Zhang, Sartori, et al., 2017).
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USP7 increases the amount of MDM2.
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USP7 increases the amount of MDM2. 6 / 6
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As shown in XREF_FIG, knockdown of USP7 reduced the levels of Mdm2 and p53, a result consistent with that of a previous study.
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Inhibition of USP7 decreases Mdm2 levels resulting in a corresponding increase in p53, inducing apoptosis.
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USP7 silencing by siRNA reduces chromatin accessibility and repair by modulating Mdm2 levels.
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USP7 (ubiquitin specific protease 7), which deubiquitinates HDM2, can lead to increased levels of HDM2 and decreased levels of p53.
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In fact, we found that HAUSP silencing in SAMe-D cells induced a decrease in Mdm2 levels (XREF_FIG), the major substrate stabilized by HAUSP, and an increase in nuclear localization of p53 after UVC treatment (XREF_FIG left panel).
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Moreover, while the levels of Mdm2 were enhanced by USP7 co-transfection, Mdm2 mediated Poleta degradation was indeed strongly rescued by USP7 overexpression (XREF_FIG).
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Modified USP7 increases the amount of MDM2. 1 / 1
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As shown by the Gu group, partial reduction of USP7 levels in several human cell lines promotes decreased levels of both MDM2 and p53, yet total abolition of USP7 stabilizes p53 levels by decreasing MDM2 [117, 118].
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USP7 affects apoptotic process
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USP7 inhibits apoptotic process.
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Compound 1, a selective inhibitor of USP7 and USP47 with moderate potency, demonstrates inhibition of USP7 in cells and induces elevated p53 and apoptosis in cancer cell lines.
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Our results indicated that USP7 knockdown also induces apoptosis (XREF_FIG).
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Interestingly USP7 inhibition induces apoptosis in a p53 independent manner in CLL.
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Furthermore, XREF_FIG showed that poly ADP-ribose polymerase (PARP) cleavage and cellular apoptosis were induced by USP7 inhibition.
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A recent study demonstrated that inhibition of ubiquitin specific protease-7 (USP7), which normally stabilizes MDM2, triggers apoptosis in bortezomib resistant MM cells, confirming the idea of p53 downregulation as a DR mechanism in MM [XREF_BIBR].
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Here we show that ubiquitin specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs.
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We showed that inhibition of USP7 in canine lymphoma and leukemia cells may cause apoptosis.
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A class of dual small molecule inhibitors of USP7 and USP47 has been identified to promote p53 activity and apoptosis in MM and B-cell leukemia cells in vitro and xenograft models.
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Notably, selective dual inhibitors of USP7 and USP47 have been synthesized and induced accumulation of p53 and apoptosis in human cancer cell lines [XREF_BIBR].
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Taken together, our results suggest that loss of USP7 function inhibits the melanoma cell cycle and promotes cell apoptosis by mediating AMPK and PI3K/Akt/FOXO signaling pathway activity.
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USP7 activates apoptotic process.
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The results indicated that overexpression of USP7 mediated apoptosis by regulating the p53-MDM2 pathway, which resulted in the upregulation of the Bad phosphorylation.
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Interestingly, the level of phosphorylated Bad was also downregulated by USP7 knockdown, and dephosphorylated Bad can interact with Bcl-2 and Bcl-xL in mitochondria, thereby inactivating these anti-apoptotic proteins and inducing apoptosis [XREF_BIBR].
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USP7 ubiquitination at Lys869 by E3 ligase TRIM27 promotes the TNF-alpha-induced apoptosis through deubiquitination of RIPK1 and the role of phosphorylation at Ser963 remains to be determined.
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USP7 downregulation promotes lung cancer cell apoptosis.
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Furthermore, direct depletion of USP7, while not altering p53 levels, promoted apoptosis and inhibited productive replication in PEL cells, indicating the overall importance of USP7 activity in HHV-8 biology.
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Likewise, HAUSP is partially cleaved during TCR mediated thymocyte apoptosis, albeit less efficiently.
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9 We also found previously that the overexpression of HAUSP leads to cancer cell apoptosis.
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USP7 was also implicated to modulate tumor growth and apoptosis in a colon carcinoma xenograft model.
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In this study, we demonstrated that loss of USP7 function inhibits cell growth by promoting cell cycle arrest and apoptosis in A375 and B16 cells.
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Collectively, these data indicated that deficiency of FOXO6 transcriptionally deregulated expression of USP7 and induced USP7 mediated apoptosis.
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USP7 activates cell population proliferation. 10 / 40
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Both of USP7 and cyclin A2 synergistically promote the proliferation and metastasis of HCC cells, reducing intracellular DNA damage.
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USP7 silencing in HL-60 cells significantly reduced cell proliferation by increasing apoptotic cell death and the proportion of cells in the G1 phase.
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Additionally , the USP7 inhibitor reduced cell proliferation , induced caspase activity and PARP cleavage , and arrested colon cancer cells in G1 .
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USP7 knockdown in colorectal cancer cells with varied TP53 status inhibits proliferation, further demonstrating that USP7 's effects can be independent of p53 [XREF_BIBR].
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USP7 knockdown or its inhibitor suppressed cell proliferation and chondrogenic differentiation but improved hypertrophic differentiation.
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In this study, we show that knockdown of Usp7 inhibits the proliferation and migration of MB cells, while Usp7 overexpression exerts an opposite effect.
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Moreover , USP7 inactivates the ubiquitinated form of Lysine-specific demethylase 1 ( LSD1 ) and promotes cell proliferation through the suppression of cell cycle arrest in brain cancer cells [ 83 ] .
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Furthermore, silencing of USP7 in 786-O ARMC5 -/- cells abrogated the enhanced cell proliferation (P =.196).
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Subsequently, using SKOV3 human ovarian adenocarcinoma cells, we showed that either USP7 or MARCH7 enhanced the proliferation and invasion abilities.
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The above evidence revealed that FOXO6 upregulated the expression of USP7 in EC to inhibit the apoptosis of tumor cells and promote their proliferation.
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USP7 bound to PRC2_complex activates cell population proliferation. 1 / 1
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We demonstrated that the USP7 and PRC2 complex drives cancer cell proliferation and tumorigenesis in vitro and in vivo.
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In addition, cell proliferation was reduced 2- to 3-fold by HAUSP or nucleolin depletion, respectively (XREF_FIG), and we observed a ~ 4 fold decrease in proliferation after HAUSP and nucleolin double-knockdown (XREF_FIG).
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Precise regulation of USP7 expression and activity is therefore necessary for maintaining proper cell proliferation, and both up- and downregulation of USP7 inhibit colon cancer cell proliferation (Be[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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In contrast, silencing USP7 significantly inhibit the cell proliferation process.
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The USP7 selective small-molecule inhibitors P5091 and P22077 inhibited cell proliferation and induced megakaryocytic differentiation in both cell lines and primary cells.
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101 HAUSP expression is enhanced by FoxO6, which inhibits proliferation of lung carcinoma.
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Similarly, upregulation of USP7 can inhibit the proliferation of esophagus cancer cells, indicating its tumor suppressing roles [XREF_BIBR].
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Importantly, in the absence of stress, both HAUSP up and downregulation inhibit cell proliferation in vitro and tumor growth in vivo due to constitutively elevated p53 levels.
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Specific silencing of USP7 using siRNA or USP7 inhibitors led to phenotypical and functional changes in M2 MPhis, favoring CD8 + T cells proliferation in vitro.
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The soft agar colony formation experiment displayed that silencing of USP7 promoted the 786-O cells ' proliferation compared to the unprocessed group, and the difference between these two groups was, respectively, statistically significant (P =.0006, P =.0004).
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Importantly, abrogation of USP7 not only sensitizes GC cells to T cell mediated killing by downregulating cell surface PD-L1 levels and attenuating its interaction with PD-1, but also suppresses the proliferation of GC cells by stabilizing P53 invitro and invivo.
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USP7 affects cell differentiation
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USP7 activates cell differentiation.
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Since USP7 acts to remove ubiquitination of histone H2B120 lysine (H2BK120Ub) and usually associates with gene transcription repression complex [XREF_BIBR, XREF_BIBR], it is unlikely that USP7 promotes osteogenic differentiation through directly regulating transcription of osteogenic associated genes.
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32 Accumulating evidence has also elucidated that up-regulation of USP7 could enhance the osteogenic differentiation of human adipose derived stem cells (hASCs) to inhibit the progression of osteogenesis, 20 suggesting that overexpression of USP7 could relieve atherosclerosis.
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Overexpression of USP7 promotes osteogenic differentiation of hASCs in vitro.
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Inactivation of Usp7 in Apc Mutated Intestinal Organoids Promotes Differentiation and Suppresses Growth.
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In conclusion, USP7 modulates the proliferation and differentiation of ATDC5 cells via the Sox9-PTHrP-PTH1R axis.
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Mechanistically, RNA-seq results showed that Usp7 negatively regulated FGSC self-renewal but positively modulated differentiation in FGSCs.
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36 Of note, our data revealed that inhibition of proteasome up-regulated expression of USP7 and KDM6B, while increased USP7 expression promoted osteoblast differentiation and autophagy, alleviating osteoporosis.
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Immunofluorescent staining showed that ectopic expression of Wt-HAUSP but not the Mt-HAUSP almost fully rescued the differentiation phenotype induced by knockdown of endogenous HAUSP with the B5 shHAUSP (XREF_FIG).
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USP7 knockdown or its inhibitor suppressed cell proliferation and chondrogenic differentiation but improved hypertrophic differentiation.
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We demonstrated that this bioactive inhibitor of USP7 significantly facilitated repression of osteogenic genes, and consequently inhibited osteogenic differentiation of hASCs.
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USP7 inhibits cell differentiation.
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Furthermore, REST overexpression in NPCs rescues the differentiation phenotype induced by HAUSP knockdown.
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Here we show that deubiquitinase HAUSP counterbalances REST ubiquitination and prevents NPC differentiation.
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Knockdown of USP7 inhibits osteogenic differentiation of hASCs in vitro.
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Indeed, quantified data indicate that HAUSP knockdown significantly increased the proportion of differentiated cells (XREF_FIG), suggesting that HAUSP deubiquitinase prevents NPC differentiation.
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In contrast, most cells targeted with shHAUSP became TUJ1 positive and only rarely remained Nestin positive (XREF_FIG, bottom panel), suggesting that targeting HAUSP induced neuronal differentiation.
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Immunofluorescent staining showed that ectopic expression of Wt-HAUSP but not the Mt-HAUSP almost fully rescued the differentiation phenotype induced by knockdown of endogenous HAUSP with the B5 shHAUSP (XREF_FIG).
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Furthermore, REST overexpression in NPCs rescued the differentiation phenotype induced by HAUSP knockdown.
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43 In conclusion, our study demonstrated that up-regulation of miR-15b could inhibit the expression of USP7, which potentially suppress the osteoblast proliferation, differentiation and autophagy to aggravate osteoporosis through inhibition of KDM6B expression.
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Here we show that the deubiquitylase HAUSP counterbalances REST ubiquitylation and prevents NPC differentiation.
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In summary, these data indicated that, analogous to its effect on hASCs, USP7 deficiency inhibits osteogenic differentiation of hBMMSCs.
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USP7 affects DNMT1
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USP7 activates DNMT1.
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USP7 activates DNMT1. 10 / 24
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Therefore, the DNA substrate was used in large excess (3-to 24-fold molar ratio), suggesting that USP7 modulates Dnmt1 's enzymatic activity rather than acting as a recruitment factor.
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In one study , USP7 was shown to stimulate DNMT1 activity in vitro and knockdown of USP7 reduced the levels of DNA methylation on several silenced genes39 .
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Deubiquitylating enzyme USP7 stimulates DNMT1 activity; and conversely, USP7-siRNA reduced DNMT1 activity and decreased MM cell viability.
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Next, we studied whether USP7 inhibition enhances activity of RRx-001 by triggering a more pronounced decrease in DNMT1 activity.
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78 DNMT1, which is frequently overexpressed in cancers, is rescued by HAUSP from UHRF1 mediated ubiquitination.
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Thus, the environment provided by USP7 greatly affects the intrinsic dynamics of DNMT1, supporting the experimental results that the intermolecular interactions are required for USP7-mediated stabilization of DNMT1 [15].
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Interestingly, binding of USP7 also increased the activity of DNMT1 in vitro, indicating that USP7 acts as a general positive factor of DNMT1, by increasing the stability and activity of the methyltransferase.
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Besides, USP7 targets the proteins of the FOXO family in lung cancer and DNMT1 in colon cancer and acts as a deubiquitinase for SUMO (small ubiquitin like modifier) [XREF_BIBR].
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A caveat in this experiment is that , given the observed interaction between USP7 and DNMT1 , depletion of USP7 would also reduce DNMT1 and thus impaired DNA methylation .
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Although the inter-molecular interaction is considered to be required for USP7-mediated stabilization of DNMT1, the detailed allosteric regulation caused by USP7 still needs to be answered.Through mapping to the DNMT1 structure, 13 mutations occur in the RFTS domain (Figure 1C), which are important for the enzymatic activity, function, and subcellular localization of DNMT1 [3].
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USP7 bound to DNMT1 activates DNMT1. 2 / 2
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The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1.
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The USP7 and Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1.
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USP7 inhibits DNMT1.
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USP7 inhibits DNMT1. 4 / 5
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Expression of shRNA resistant wild-type Usp7 in Usp7 depleted cells reduced the size of Dnmt1 nuclear foci, but catalytically-inactive Usp7 (C223S) failed to do so.
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Loss of USP7 enhances DNMT1 association with replication sites As increased histone ubiquitination is observed in USP7 KO cells , we next examined if loss of USP7 results in an increase of DNMT1 recruitment in S phase of cell cycle .
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Furthermore, loss of HAUSP combined with inhibition of HDAC activity had a synergistic effect on DNMT1 protein stability, because treatment of HAUSP knockout cells with various HDAC inhibitors reduced DNMT1 abundance to nearly undetectable amounts (XREF_FIG and XREF_SUPPLEMENTARY).
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Thus , consistent with an increased DNA methylation phenotype , loss of USP7 apparently enhanced DNMT1 association with replicating DNA , a result consistent with a previous study44 .
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Modified USP7 inhibits DNMT1. 1 / 1
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Overexpression of USP7 partially, but significantly attenuated ursolic acid induced cell death as well as downregulation of MDM2, UHRF1 and DNMT1.
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USP7 increases the amount of DNMT1.
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Modified USP7 increases the amount of DNMT1. 1 / 1
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The overexpression of USP7 WT or USP7 M3, but not USP7 M1 or USP7 CS, markedly increased the protein level of DNMT1 in HEK293T cells (XREF_FIG).
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USP7 increases the amount of DNMT1. 1 / 1
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Therefore, Usp7 promotes DNA methylation by increasing the amount of Dnmt1 24.
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USP7 decreases the amount of DNMT1.
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USP7 decreases the amount of DNMT1. 1 / 1
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USP7 WT, but not USP7 CS, largely decreased the ubiquitination level of DNMT1 in vitro (XREF_SUPPLEMENTARY).
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USP7 affects REST
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USP7 activates REST.
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USP7 activates REST. 8 / 19
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HAUSP knockdown in NPCs decreases REST and induces differentiation.
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Here, we demonstrated that deubiquitinase HAUSP (Herpesvirus Associated Ubiquitin Specific Protease, also known as Ubiquitin Specific Protease 7, USP7) XREF_BIBR, XREF_BIBR prevents REST degradation through deubiquitination and promotes NPC maintenance.
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In contrast, HAUSP (the herpesvirus associated ubiquitin specific protease, also known as USP7) had been shown to suppress REST degradation through a deubiquitination process [XREF_BIBR].
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In contrast, HAUSP overexpression up-regulates REST by overriding beta-TrCP-mediated ubiquitination.
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Functional disruption of HAUSP in NPCs reduces REST protein and induces neuronal differentiation.
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HAUSP knockdown in NPCs decreased REST and induced differentiation.
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In contrast, HAUSP overexpression upregulates REST by overriding beta-TrCP-mediated ubiquitylation.
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Theoretically, HAUSP might indirectly modulate REST through transcriptional control but we confirmed that HAUSP knockdown did not alter REST mRNA expression on RT-PCR analysis (XREF_FIG).
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USP7 inhibits REST.
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USP7 inhibits REST. 1 / 8
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This was born out using a second independent USP7 siRNA pool that neither reduced REST nor potentiated the effect of USP15 knockdown in A549 cells under normal growth conditions (XREF_SUPPLEMENTARY).
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USP7 increases the amount of REST.
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USP7 increases the amount of REST. 3 / 3
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As HAUSP knockdown reduced REST protein levels and promoted NPC differentiation, we further examined whether ectopic expression of Wt-HAUSP overrides shHAUSP induced differentiation.
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HAUSP positively regulates REST protein levels in neural progenitor cells.
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Collectively, these data demonstrate that HAUSP deubiquitinase positively regulates REST protein levels.
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Modified USP7 increases the amount of REST. 2 / 2
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In contrast, ectopic expression of HAUSP (HA tagged HAUSP) in NPCs increased REST protein levels (XREF_SUPPLEMENTARY).
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Ectopic expression of Wt-HAUSP but not the Mt-HAUSP decreased REST ubiquitination and increased REST protein levels (XREF_FIG; XREF_SUPPLEMENTARY).
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USP7 decreases the amount of REST.
| 1
Modified USP7 decreases the amount of REST. 1 / 1
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Ectopic expression of Wt-HAUSP but not the Mt-HAUSP decreased REST ubiquitination and increased REST protein levels (XREF_FIG; XREF_SUPPLEMENTARY).
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TP53 affects USP7
| 26
TP53 activates USP7.
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TP53 activates USP7. 10 / 15
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To determine whether there was increased apoptosis due to p53 activation in hausp knockout embryos, a TUNEL (TdT mediated dUTP Nick-End Labeling) assay was performed on wild-type and hausp knockout embryos of both days E6.5 (XREF_FIG) and E7.5 (XREF_FIG).
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Interestingly, the level of Mdm4 showed slight increase in hausp knockout MEFs (XREF_FIG, lane 6 versus lane 5), suggesting p53 activation in hausp knockout MEFs was mainly because of downregulation of Mdm2.
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The results showed that knockout of p53 did not rescue the lethality of the hausp knockout.
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10, 13, 14 The identification of these substrates indicates that USP7 controls additional vital cellular functions beyond those mediated by p53 stability.
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We therefore observed p53 independent induction of p21 protein that was followed by cell-cycle arrest in G1 phase, as previously described.
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Once again, the current study demonstrated the essential roles of p53 independent functions of HAUSP, indicated by the inability to rescue the neonatal lethality of hausp FL/FL; nes-cre mice by concomitant deletion of p53.
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Loss of TP53 rescues the effects of MDM2, MDM4, PPM1D, and USP7 inhibition.
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Hdm2 is preferentially targeted by USP7 over p53 under normal unstressed conditions; however, USP7 targets p53 in response to DNA damage.
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Hausp knockout was partially rescued by p53 knockout.
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Although deletion of p53 did not completely rescue the embryonic lethality of the hausp knockout, embryonic development was extended in both hausp and p53 double knockout embryos.
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TP53 bound to SGTA activates USP7. 1 / 1
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In a well studied example, the N-terminal domain of the human UBP called herpesvirus associated ubiquitin specific protease ([HAUSP] USP7) binds the p53 tumor suppressor, allowing HAUSP to cleave polyubiquitin-p53 conjugates and, thereby, limit p53 degradation.
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TP53 bound to USP7 activates USP7. 1 / 1
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Conflicting studies show that binding of p53 to USP7 either promotes the deubiquitination and subsequent stabilization of p53 [XREF_BIBR, XREF_BIBR] or that disruption of USP7 stabilizes p53 [XREF_BIBR, XREF_BIBR].
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TP53 inhibits USP7.
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TP53 inhibits USP7. 5 / 6
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XREF_BIBR, XREF_BIBR The p53 staining was weak but was detectable in some of the cells in hausp FL/FL; nes-cre cortex at day E12.5 (data not shown), indicating the onset of the accumulation of p53 following depletion of HAUSP protein.
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P53 levels were increased by compound 4 in all three cell lines, confirming its inhibition of USP7.
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Concomitant deletion of p53 partially rescued the developmental defects in hausp nes-cre conditional knockout mice, providing direct evidences for p53 dependent functions of HAUSP.
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These results suggested that although deletion of p53 failed to rescue the neonatal lethality of hausp FL/FL; nes-cre mice, survival of neural cells and brain development were largely restored in the absence of p53.
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As shown in XREF_FIG, both p53 and Mdm2 had decreased half-lives in hausp heterozygote MEF cells (lanes 5-8) compared with that in wild-type MEF cells (lanes 1-4).
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TP53 bound to TSPYL5 inhibits USP7. 1 / 1
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In HEK293 cells, we observed that TSPYL5 could competitively bind to the N-terminal domain of deubiquitylase USP7 in conjunction with p53 and reduce the protective effects of USP7 on p53, resulting in ubiquitin mediated degradation of p53, and that the co-transfection of TSPY1 and TSPYL5 enhanced this effect.
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TP53 deubiquitinates USP7.
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TP53 deubiquitinates USP7. 2 / 2
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Knockdown of the p53 deubiquitinating enzyme USP7 and HAUSP also reverses the supervillin phenotype, blocking the increase in p53 levels seen after supervillin knockdown and accentuating the decrease in p53 levels triggered by supervillin overexpression.
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It stabilizes p53 and induces p53-dependent apoptosis in cancer cells through inhibition of the p53-deubiquitinating enzyme USP7 [92].
| PMC
TP53 increases the amount of USP7.
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TP53 increases the amount of USP7. 1 / 1
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Their results indicated that p53 loss did not completely rescue the loss of HAUSP, leaving open a role for PTEN in HAUSP-cKO mice.
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USP7 affects FOXP3
1 | 22
USP7 activates FOXP3.
1 | 7
USP7 activates FOXP3. 5 / 5
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We now report that both Tip60 and Foxp3 proteins are subject to ubiquitination and proteasomal degradation, whereas the actions of a deubiquitinating (DUB) enzyme, ubiquitin specific protease, Usp7 (also known as HAUSP), counteract these events and promote Tip60 and Foxp3 stability and, consequently, Treg suppressive function.
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Hence, Usp7 can promote assembly of higher order complexes of Foxp3, including formation of Foxp3 dimers that are essential for optimal Foxp3 binding to DNA in Treg cells, whereas Usp7i treatment can disrupt assembly of such complexes.
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USP7 knockdown or inhibition by a DUB inhibitor reduces the level of Foxp3 protein and compromises the function of Treg cells 273.
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Indeed, USP7 decreased the rate of degradation of Foxp3 (XREF_SUPPLEMENTARY).
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The deubiquitinase USP7 is upregulated in Tregs and prolongs the half-life of FOXP3 protein by reducing its ubiquitin mediated degradation rate.
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USP7 activates FOXP3. 2 / 2
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Knockdown of USP7 or DUB inhibitor induced the loss of Foxp3 protein in Tregs.
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Control of ubiquitination of the FOXP3 protein by enhancing its acetylation (HDAC inhibition, p300 induction), inhibiting cytokine-induced Stub1 levels and enhancing USP7 expression, prevents FOXP3 degradation.
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USP7 activates FOXP3. 1 / 1
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Foxp3 is a critical Tx for Treg polarization and regulated by one of many mechanisms, including ubiquitination-dependent degradation. Deubiquitinase USP7 decreases Foxp3 polyunibiutination and stabilize Foxp3, thus increases Treg-suppressive capacity.
USP7 increases the amount of FOXP3.
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USP7 increases the amount of FOXP3. 4 / 4
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By contrast, overexpressing USP7 in T reg cells increases FOXP3 protein levels and augments T reg cell activity 104.
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USP7 Mediated Foxp3 Deubiquitination Results in Increased Foxp3 Protein Expression.
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To determine whether USP7 mediated deubiquitination results in increased Foxp3 protein amounts, we assessed Foxp3 expression in HEK 293T cells that were cotransfected with Foxp3 and USP7.
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Foxp3 K22xR protein amounts were not increased by the cotransfection of USP7, indicating that USP7 stabilizes Foxp3 expression by direct deubiquitination.
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USP7 increases the amount of FOXP3. 2 / 2
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The knockdown of USP7 decreased the levels of endogenous FOXP3 and diminished the Treg suppressive activity while ectopic expression of USP7 increased FOXP3 expression by preventing its degradation.
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Our present findings suggest that targeting factors such as USP44 and USP7 that promote FOXP3 expression at the protein level is a strategy that offers exciting possibilities for the fine tuning of immune responses in cancer.
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USP7 bound to FOXP3 increases the amount of FOXP3. 1 / 1
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In a previous study, van Loosdregt et al. (2013) showed that USP7 interacted with and deubiquitinated Foxp3, thereby increasing Foxp3 protein levels.
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Modified USP7 increases the amount of FOXP3. 1 / 1
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Ectopic expression of USP7 decreased Foxp3 polyubiquitination and increased Foxp3 expression.
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USP7 decreases the amount of FOXP3.
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USP7 decreases the amount of FOXP3. 3 / 3
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In fact, USP7 expression is highly upregulated in FOXP3 + Tregs, whereas USP7 downregulation or inhibition causes loss of FOXP3 and impairs Treg functions.
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To further validate that USP7 directly reduced Foxp3 protein expression because of enhanced degradation and not indirectly through additional mechanisms, we analyzed the activation status of multiple signaling pathways in the presence or absence of USP7.
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Excitingly, the authors of this study 82 also found that the in vivo administration of a specific USP7 antagonist inhibited FOXP3 expression and the suppressive activity of T reg cells in tumour bearing mice.
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Modified USP7 decreases the amount of FOXP3. 1 / 1
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Ectopic expression of USP7 decreased Foxp3 polyubiquitination and increased Foxp3 expression.
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USP7 decreases the amount of FOXP3. 1 / 1
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The knockdown of USP7 decreased the levels of endogenous FOXP3 and diminished the Treg suppressive activity while ectopic expression of USP7 increased FOXP3 expression by preventing its degradation.
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USP7 inhibits FOXP3.
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USP7 inhibits FOXP3. 1 / 1
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USP7 decreased immune activation by binding to and stabilizing FoxP3 in regulatory T cells, perhaps serving to counteract the actions of Stub1 and Cbl-b, which can promote FoxP3 ubiquitylation.
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USP7 inhibits FOXP3. 1 / 1
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Combined USP7 and USP44 knockdown, however, even further enhanced FOXP3 degradation (Fig XREF_FIG D, left panel).
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USP7 affects KDM6B
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USP7 activates KDM6B.
| 4 8
USP7 activates KDM6B. 10 / 12
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These data concluded that co-expression of USP7 enhanced the stability of KDM6B to promote the KDM6B expression.
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3.4 USP7 enhanced the stability of KDM6B to promote KDM6B expression.
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Combining previous studies with our results, a regulatory network could be proposed in the antagonizing atherosclerosis progression that depletion of miR-15b promoted USP7 expression to up-regulate KDM6B.
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This proved that FOXO6 upregulates the expression of JMJD3 and CLU by mediating USP7 , which was confirmed by observations of neoplasia growth in vivo .
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37 , 38 In addition , a recent study has confirmed that USP7 could promote KDM6B expression by enhancing KDM6B stability .
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USP7 , importantly , strengthened the stability of KDM6B and promoted KDM6B expression .
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Based on these reports, we speculated that the USP7 mediated JMJD3 and CLU axis may be involved in the regulation of FOXO6 in EC.
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These data supported our proposal that USP7 targeted JMJD3 for deubiquitination to improve JMJD3 protein stability.
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Combining previous studies with our results , a regulatory network could be proposed in the antagonizing atherosclerosis progression that depletion of miR-15b promoted USP7 expression to up-regulate KDM6B .
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37 In this study, we found that USP7 enhanced the stability of KDM6B to promote KDM6B expression inhibited the ubiquitination, while miR-15b inhibits USP7 expression in osteoporosis.
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USP7 inhibits KDM6B.
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USP7 inhibits KDM6B. 4 / 4
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Additionally , JMJD3 and CLU expression was not increased by knockdown of USP7 in the FOXO6 overexpressed cells , whereas CLU expression was decreased by knockdown of JMJD3 , and USP7 expression could still be regulated by FOXO6 simultaneously .
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In addition , when treated with cycloheximide ( CHX ) , a protein synthesis inhibitor , upregulation of USP7 decreased the degradation of JMJD3 ( Figure 4E ) .
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In addition, when treated with cycloheximide (CHX), a protein synthesis inhibitor, upregulation of USP7 decreased the degradation of JMJD3 (XREF_FIG E).
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Impressively, our experimental data elucidated that overexpressed USP7 significantly inhibited the degradation rate of JMJD3.
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USP7 increases the amount of KDM6B.
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USP7 increases the amount of KDM6B. 4 / 4
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37, 38 In addition, a recent study has confirmed that USP7 could promote KDM6B expression by enhancing KDM6B stability.
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USP7, importantly, strengthened the stability of KDM6B and promoted KDM6B expression.
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As expected, co-expression of USP7 increased the JMJD3 levels but decreased ubiquitinated JMJD3 levels (XREF_FIG D).
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XREF_BIBR Similarly, our further mechanistic investigations demonstrated that overexpression of USP7 increased the protein level of JMJD3 and its ubiquitin modification level.
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USP7 decreases the amount of KDM6B.
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USP7 decreases the amount of KDM6B. 1 / 1
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Additionally, JMJD3 and CLU expression was not increased by knockdown of USP7 in the FOXO6 overexpressed cells, whereas CLU expression was decreased by knockdown of JMJD3, and USP7 expression could still be regulated by FOXO6 simultaneously.
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USP7 decreases the amount of ubiquitinated KDM6B. 1 / 1
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As expected, co-expression of USP7 increased the JMJD3 levels but decreased ubiquitinated JMJD3 levels (XREF_FIG D).
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USP7 affects Wnt
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USP7 activates Wnt.
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USP7 activates Wnt. 10 / 13
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Another group recently proposed, using a small interfering RNA (siRNA) knockdown strategy, that USP7 enhances Wnt signaling through RNF220 dependent beta-catenin deubiquitination, which is inconsistent with our current findings.
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In colon cancer cells with stimulated Wnt signaling, knockdown of RNF220 or USP7 impairs Wnt signaling and expression of Wnt target genes, suggesting a potentially novel role of RNF220 in Wnt related tumorigenesis.
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Transient targeting of USP7 in APC4 cells immediately after transfection significantly suppressed Wnt transcriptional activity, while such suppression was gradually lost upon colony picking (XREF_SUPPLEMENTARY B).
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Overall, USP7 overexpression could promote OS cell metastasis by activating the Wnt and beta-catenin signalling pathway by inducing EMT, suggesting that USP7 is a potential therapeutic target for OS.
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In summary, USP7 inhibition by CRISPR targeting or treatment with two different small molecules consistently suppresses aberrant Wnt activation in CID-loss APC mutant cells.
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USP7 also activates Wnt signaling in adenomatous polyposis coli gene ( APC ) - mutated colorectal cancer through beta-catenin deubiquitination ( Novellasdemunt et al. 2017 ) .
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Studies have found that USP7 inhibitors P5091 and Parthenolide inhibits Wnt signaling and colorectal tumor growth ; specific inhibitor HBX 19818 can selectively reduce the activity of USP7 ; USP7 small-molecule inhibitors P5091 and P22077 can induce tumor cell apoptosis by enhancing intracellular oxidative stress response and endoplasmic reticulum stress response [ 40,188,189,190,191 ] .
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beta-Catenin (Ser33Y) expression significantly rescued the number of colonies formed as well as the Wnt transcriptional activity mediated by USP7 CRISPR mutation in both cells (XREF_FIG H and XREF_SUPPLEMENTARY L), suggesting that the growth defect upon USP7 loss is due to modulation of Wnt signaling.
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Specific inhibitors of USP7 (P5091 and parthenolide) were shown to attenuate Wnt and beta-catenin-induced proliferation and migration and suppress tumor growth in HCT116 xenograft mouse models and are yet to be examined in clinical settings [XREF_BIBR, XREF_BIBR].
| PMC
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Targeting USP7 with Small-Molecule Inhibitors Suppresses Wnt Activation in CRCs Carrying CID Deleted APC Mutations.
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USP7 bound to CTNNB1 activates Wnt. 1 / 1
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Notably, USP7 can directly bind with beta-catenin to activate the Wnt and beta-catenin signalling pathway and induce epithelial-mesenchymal transition (EMT) of OS cells.
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USP7 bound to RNF220 activates Wnt. 1 / 1
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The RNF220 and USP7 complex deubiquitinates beta-catenin and enhances canonical Wnt signaling.
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USP7 inhibits Wnt.
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USP7 inhibits Wnt. 6 / 6
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On the other hand, incomplete KO of USP7 was sufficient to inhibit Wnt signaling and suppress tumor growth.
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We confirmed that targeting USP7 can suppress tumor growth invivo by inhibiting Wnt activation.
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USP7 inhibits Wnt and beta-catenin signaling through promoting stabilization of Axin.
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USP7 represses Wnt and beta-catenin signaling through stabilization of Axin, which is a part of the destruction complex that inhibits beta-catenin.
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The results showed that USP7 mediated Wnt activation in CRC is a reversible process.
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USP7 knockdown inhibits the proliferation of CRC cells with different p53 status, and USP7 inhibition by its inhibitor P5091 attenuates the activity of Wnt signaling via enhanced ubiquitination and the subsequent degradation of beta-catenin.
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USP7 affects USP7
| 1 11
USP7 decreases the amount of USP7.
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USP7 decreases the amount of USP7. 2 / 7
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The expressions of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was attenuated by USP7 KD or USP7 inhibitor (XREF_FIG), were significantly enhance by the H 2 O 2 treatment as shown in western blotting results.
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ELISA and Western blotting results indicated that USP7 overexpression significantly increased IL-1beta and IL-18 levels as well as the expression of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was decreased by USP7 KD or apocynin (XREF_FIG).
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Modified USP7 decreases the amount of USP7. 1 / 1
| 1
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Notably, expression of the HAUSP triple mutant (Y243F/Y878F/Y947F), which bears mutants on three tyrosine residues phosphorylated by p210 BCR and ABL, reduced HAUSP phosphorylation levels in HEK 293T when compared to those of HAUSP WT, as observed with p210 BCR and ABL.
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USP7 increases the amount of USP7.
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USP7 increases the amount of USP7. 5 / 5
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USP7 knockdown by shRNA reduced total cellular USP7 levels as well as USP7 promoter occupancy in p53 WT cells.
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USP7 knockdown by shRNA reduced total cellular USP7 levels (XREF_FIG) as well as USP7 promoter occupancy in p53 wt cells (XREF_FIG).
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HAUSP knockdown not only reduced HAUSP expression level but also decreased nucleolin level (XREF_FIG).
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In the Jurkat cell line, we observed an interesting phenomenon that reduction in USP7 transcription caused by mono-allelic knock-out of USP7 did not reduce USP7 protein level.
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ELISA and Western blotting results indicated that USP7 overexpression significantly increased IL-1beta and IL-18 levels as well as the expression of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was decreased by USP7 KD or apocynin (XREF_FIG).
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USP7 inhibits USP7.
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USP7 inhibits USP7. 2 / 4
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ROS assay showed that H 2 O 2 elevated ROS production which was abolished by USP7 KD or USP7 inhibition ( xref ).
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Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.
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USP7 activates USP7.
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USP7 activates USP7. 2 / 4
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Furthermore, we revealed that ECT2 depletion impaired the upregulation of endogenous USP7 induced by forced expression of GFP-USP7.
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Taken together, these results suggested that ECT2 counteracts the polyubiquitination of USP7 thus promotes USP7 stabilization in a GEF activity independent manner.
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USP7 affects Ubiquitin
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USP7 activates Ubiquitin.
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USP7 activates Ubiquitin. 8 / 10
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They include the potential recruitment of DUBs for the stabilization of beta-catenin in Epstein-Barr virus (EBV)-infected B cells, and the specific targeting of the cellular DUB ubiquitin specific protease 7 (USP7) by the Epstein-Barr nuclear antigen 1 (EBNA1) and the herpes simplex virus type 1 (HSV-1) regulatory protein ICP0.
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Usp7 is thought to exist in equilibrium between inactive and active forms, and its activity is enhanced allosterically by the metabolic enzyme, GMPS, which binds and activates the HUBL domain of Usp7, increasing the ubiquitin binding and catalytic activity of Usp7 by 100-fold.
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Here we present structural, biochemical, and biophysical analyses elucidating the molecular mechanism by which the C-terminal 19 amino acids of USP7 (residues 1084-1102) enhance the ubiquitin cleavage activity of the deubiquitinase (DUB) domain.
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First, we tested whether USP7 could stimulate p53 function in a ubiquitin independent manner during conditions of cellular stress such as DNA damage.
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USP7 deubiquitinase promotes ubiquitin dependent DNA damage signaling by stabilizing RNF168.
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Indeed, such effects were reported for HAUSP mediated ubiquitin removal of PTEN (phosphatase and tensin homologue deleted in chromosome 10) and FOXO (Forkhead box O) 4.
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The specificity of SJB was confirmed by various experiments : first, we show that SJB potently and selectively block USP1 activity without inhibiting other DUBs (USP2/USP5/USP7/USP14/UCH37); second, SJB inhibited binding of USP1 with HA-Ub-VS probe, but it did not affect labeling of other DUBs with probe; and third, SJB inhibited USP1, but not USP2 or USP7, triggered cleavage of ubiquitin tetramer chains.
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Regulation of USP7 by viruses may enable fine tuning of ubiquitin signals on targeted cellular proteins and may indirectly affect damage responses.
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USP7 inhibits Ubiquitin.
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USP7 inhibits Ubiquitin. 7 / 7
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Importantly, these effects were independent of p53 status and could be rescued by the MG132 proteasome inhibitor (XREF_FIG), suggesting that USP7 prevents ubiquitin mediated degradation of TRIM27 by the proteasome.
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Ubiquitin ligase activity is therefore required for mRNA degradation and can be prevented either by removal of the RING (RINGless MEX-3C) or by overexpression of the USP7 DUB.
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Importantly, these effects were independent of p53 status and could be rescued by the MG132 proteasome inhibitor, suggesting that USP7 prevents ubiquitin mediated degradation of TRIM27 by the proteaso[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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However, it is still possible that USP7 may antagonize the action of FBXL21 by cleaving the ubiquitin chain (s) formed by FBXL21.
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As increased TAL1 oncogenic activity was also evident in the accelerated cell growth observed after CRISPR knock-out of half of the USP7 loci in T-ALL cell lines, we hypothesize that USP7 haploinsufficiency in T-ALL down-regulates the ability of this deubiquitylating enzyme to remove ubiquitin from E-proteins, leads to enhanced TAL1 heterodimer formation, which favors TAL1 mediated thymocyte transformation.
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Although USP7, like all DUBS, deconjugates ubiquitin from several target proteins, inhibition of USP7 promotes the degradation of its primary cellular target, HDM2, resulting in net p53 stabilization and activation [30, 42, 43] .
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This class of allosteric inhibitors has been demonstrated to bind to the ' palm ' region of the USP7 catalytic domain thereby impeding ubiquitin binding (orange, XREF_FIG) [XREF_BIBR, XREF_BIBR].
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Modified USP7 inhibits Ubiquitin. 1 / 1
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CRY1 is ubiquitinated in this assay (XREF_FIG, CRY1 ub smear in lane 2), and co-expression of USP7 reduced CRY1 ubiquitination (ubiquitin smear in lane 3 compared to lane 2).
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USP7 increases the amount of Ubiquitin.
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USP7 increases the amount of Ubiquitin. 1 / 1
| 1
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XREF_BIBR Similarly, our further mechanistic investigations demonstrated that overexpression of USP7 increased the protein level of JMJD3 and its ubiquitin modification level.
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FOXO6 affects USP7
| 4 1 14
FOXO6 activates USP7.
| 4 1 6
FOXO6 activates USP7. 10 / 11
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To verify whether FOXO6 promoted the progression of EC through JMJD3 and CLU by mediating USP7, we first constructed FOXO6 overexpression cell lines combined with or without si-USP7 plasmid.
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Collectively , these data indicated that deficiency of FOXO6 transcriptionally deregulated expression of USP7 and induced USP7-mediated apoptosis .
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XREF_BIBR We hypothesized that FOXO6 initiates the activation of USP7 in EC.
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A previous study xref showed that USP7 transcriptional activation by FOXO6 suppresses lung cancer progression and that USP7 inhibited cell proliferation in EC. xref We hypothesized that FOXO6 initiates the activation of USP7 in EC.
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XREF_BIBR Current experimental data showed that JMJD3 overexpression reduced the accumulation of EZH2 in the CLU promoter region, indicating that FOXO6 was able to mediate USP7 to regulate the stability of JMJD3, which is a competitor for EZH2 in binding with the promoter region of CLU, the downstream target gene, and then participate in regulating the tumorigenesis and development of EC.
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The above evidence revealed that FOXO6 upregulated the expression of USP7 in EC to inhibit the apoptosis of tumor cells and promote their proliferation .
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Silencing of FOXO6 physically reduced USP7, resulting in promoted EC apoptosis.
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FOXO6 promoted USP7 expression , which enhanced JMJD3 ubiquitination and promoted CLU expression .
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A previous study XREF_BIBR showed that USP7 transcriptional activation by FOXO6 suppresses lung cancer progression and that USP7 inhibited cell proliferation in EC.
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In addition , FOXO6 knockdown suppressed the expression of USP7 and that of apoptosis-related protein c-CASP3 .
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FOXO6 increases the amount of USP7.
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FOXO6 increases the amount of USP7. 6 / 6
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Collectively, these data indicated that FOXO6 promoted the proliferation and angiogenesis of EC by mediating USP7 expression via the JMJD3 and CLU pathway.
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The above evidence revealed that FOXO6 upregulated the expression of USP7 in EC to inhibit the apoptosis of tumor cells and promote their proliferation.
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In addition, FOXO6 knockdown suppressed the expression of USP7 and that of apoptosis related protein c-CASP3.
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101 HAUSP expression is enhanced by FoxO6, which inhibits proliferation of lung carcinoma.
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Furthermore, silencing of FOXO6 expression attenuated the mRNA and protein levels of USP7, but it enhanced apoptotic protein cleaved-caspase3 (c-CASP3) expression (XREF_FIG C and 3D).
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USP7 expression is also enhanced by FOXO6, which inhibits proliferation of lung carcinoma [XREF_BIBR].
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Modified FOXO6 increases the amount of USP7. 1 / 1
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Furthermore, ectopic FOXO6 expression induced the expression of ubiquitin-specific-processing protease 7 (USP7).
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FOXO6 inhibits USP7.
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FOXO6 inhibits USP7. 1 / 1
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XREF_BIBR Interestingly, FOXO6 inhibits tumor cell proliferation via upregulation of ubiquitin specific processing protease 7 (USP7) in lung cancer.
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GMPS affects USP7
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GMPS activates USP7. 10 / 18
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Therefore, this suggests that for some USPs the KG FP reagent may be a better substrate, and provide more relevant kinetic parameters.This study confirmed that the modulator UAF1 activates USP1, USP12[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Activation of USP7 by GMPS against a minimal substrate changes only k cat.
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The parallels between GMPS and ICP0 binding to USP7 raise the possibilities that ICP0 might mimic GMPS in stimulating USP7 activity or alternatively that it might interfere with GMPS stimulation of USP7 activity by competing with GMPS for USP7.
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GMPS is an allosteric activator of USP7 and stabilizes its active state resulting in hyperactivation of USP7 54.
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Activation of USP7 by GMPS against a minimal substrate changes only k cat ( xref ).
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For example, USP1, USP12, and USP46 are activated by the WD40-repeat containing UAF1, and USP7 is activated by GMPS (Cohn et al., 2007, 2009; Faesen et al., 2011; van der Knaap et al., 2005).
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This shows that GMPS can allosterically activate USP7 by binding to HUBL-123, stabilizing the contact between HUBL-45 and USP7CD, thus promoting the activated state.We show here that the C-terminal HU[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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A USP7 cofactor called GMPS that strongly augments USP7 activity was recently identified in Drosophila (van der Knaap et al., 2005).
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However, we show that binding of GMPS can further activate USP7.
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The GMP synthetase (GMPS) was found to interact with and stimulate USP7 activity through its binding to the first three UBLs in USP7 (HUBL-123) and promote an " on-state " in USP7.
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USP7 affects Neoplasm Invasiveness
| 1 17
USP7 activates Neoplasm Invasiveness.
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USP7 activates Neoplasm Invasiveness. 10 / 17
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Furthermore, our cellular experiments showed that USP7 can directly enhance the proliferation and invasion of HCC cells, demonstrating its potential as a drug target.
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USP7 could promote the viability and invasion of OC cells.
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These results indicated that USP7 potentially participates in EMT to promote NSCLC cell invasiveness.
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Subsequently, using SKOV3 human ovarian adenocarcinoma cells, we showed that either USP7 or MARCH7 enhanced the proliferation and invasion abilities.
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Functionally, USP7 overexpression promoted cell growth and invasion via deubiquitination of EZH2.
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We found that USP7 knockdown significantly inhibited cell invasiveness.
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Cellular studies showed that USP7 could enhance the proliferation, migration, and invasion capacities of HCC cells, thereby promoting tumor progression.
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Similarly, overexpression USP7 enhanced the invasion ability of HCC cells as showed by the Matrigel-Transwell assay, while USP7-knockdown attenuated the invasion process (XREF_FIG).
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Similarly, USP7 overexpression in patients with epithelial ovarian cancer was found to induce cell invasion and correlate with poor survival.
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The RNA inteference and overexpression assays indicated that USP7 can positively regulate the ovarian cell vitality and invasion process.
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USP7 inhibits Neoplasm Invasiveness.
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Consistently, downregulation of USP7 inhibited cell migration and invasion in cancer.
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USP7 affects PTEN
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USP7 activates PTEN.
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USP7 activates PTEN. 8 / 9
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XREF_BIBR Moreover, USP7 may contribute to cancer by modulating the nuclear localization of PTEN.
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27 Changes in subcellular localization of PTEN mediated by HAUSP are crucial in certain leukemias.
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XREF_BIBR, XREF_BIBR Daxx localization to PODs increases PTEN nuclear localization and PTEN tumor suppressor activity by inhibiting HAUSP mediated PTEN deubiquitinylation.
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Unlike previous USPs, USP7 modulates the localization and conformational structure editing of the well-known tumor suppressors p53 and PTEN.
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First, HAUSP (a DUB previously known to modify several important genes including p53 and FOXO4) overexpression leads to a predominantly nuclear excluded PTEN.
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Unlike PML, PML-RARalpha overexpression was not able to prevent HAUSP mediated deubiquitinylation of PTEN (XREF_FIG).
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Additionally, knock-down of HAUSP by RNA interference (RNAi) increased PTEN monoubiquitinylation (XREF_FIG and XREF_SUPPLEMENTARY).
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To further investigate this possibility we tested the ability of PML to oppose HAUSP mediated PTEN deubiquitinylation.
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USP7 activates PTEN-K13E. 1 / 1
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In agreement with this hypothesis, PTEN K13E was similarly modulated by HAUSP levels (XREF_SUPPLEMENTARY).
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USP7 inhibits PTEN.
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USP7 inhibits PTEN. 7 / 7
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Since we previously demonstrated that USP7 plays an essential role in the regulation of PTEN compartmentalization in CML [XREF_BIBR, XREF_BIBR], we sought to investigate whether USP7 functionally inactivates PTEN in CLL through PTEN nuclear exclusion.
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From a functional point of view, USP7 inhibition restores PTEN localization in CLL.
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Our data demonstrate that USP7 is responsible for PTEN nuclear exclusion with consequent impairment of its tumor suppressive functions and that USP7 inhibition restores PTEN nuclear pool and its oncosuppressive activity in the context of CLL.
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USP7 has been shown to inactivate several tumor suppressors including P53, FOXO4 (Forkhead box O4) and PTEN (phosphatase and tensin homolog deleted on chromosome ten) through different mechanisms, which lead to tumorigenesis [XREF_BIBR - XREF_BIBR].
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Therefore, we speculated that USP7 inhibition may promote PTEN reactivation and consequently cancer selective apoptotic induction, without affecting normal cells.
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Since we previously demonstrated that USP7 plays an essential role in the regulation of PTEN compartmentalization in CML [ xref , xref ], we sought to investigate whether USP7 functionally inactivates PTEN in CLL through PTEN nuclear exclusion.
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In contrast, USP7 reduced nuclear localization of PTEN in PC3 cells without affecting total PTEN protein levels (XREF_FIG), consistent with previously reported findings 18.
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USP7 affects cell growth
| 1 13
USP7 activates cell growth.
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USP7 activates cell growth. 10 / 10
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Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo.
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Functionally, USP7 overexpression promoted cell growth and invasion via deubiquitination of EZH2.
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HAUSP strongly stabilizes p53 even in the presence of excess Mdm2, and also induces p53 dependent cell growth repression and apoptosis.
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USP7 silencing in MEC-1 cells abrogated cell growth, corroborating the bona fide data we obtained with the inhibitor.
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These experiments showed that USP7 haploinsufficiency decreases the E protein activity of E2A and HEB and promotes T-ALL cell growth.
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In particular, pharmaceutical inhibition of USP7 by the small molecule P22077 attenuated PDAC cell growth and induced cell death in vitro and in vivo.
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USP7 haploinsufficiency promotes T-ALL cellular growth.
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We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo.
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Our finding that USP7 inhibition in vitro and in vivo significantly suppresses leukemic cell growth, alone and in combination with chemotherapy, independently of p53 status supports this notion.
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In this study, we demonstrated that loss of USP7 function inhibits cell growth by promoting cell cycle arrest and apoptosis in A375 and B16 cells.
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USP7 inhibits cell growth.
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USP7 inhibits cell growth. 4 / 5
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Thus, HAUSP appears to play multiple roles in regulating the p53-MDM2 pathway as well as in EBV induced tumor cell survival, and is hence a potential chemotherapeutic target for p53 mediated suppression of tumor cell growth.
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Tumor cell growth, volume, and weight were decreased by the depletion or inhibition of HAUSP XREF_BIBR XREF_BIBR.
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In fact, total knock-out of USP7 also blocks cell growth in T-ALL cells, emphasizing the dosage-dependence of heterozygous USP7 LOF mutations in pediatric T-ALL.
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In Multiple Myeloma (MM), where patients with activated NFKB signaling though NEK2 have poorer outcomes, USP7 inhibitors effectively inhibit myeloma cell growth and overcome NEK2-induced and NEK2- acquired drug resistance in xenograft models [ xref ].
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USP7 affects cell death
| 1 13
USP7 inhibits cell death.
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USP7 inhibits cell death. 9 / 9
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Having analyzed cell cycle progression, we investigated if USP7 inhibition causes any particular type of cell death.
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USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix.
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USP7 knockdown effectively induced cell death in several cancer cells of lung , prostate , and cervix .
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In this paper, we demonstrate that inhibition of deubiquitinylase USP7 significantly reduces cell proliferation in vitro and in vivo, blocks DNA replication progression and increases cell death in AML.
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In particular, pharmaceutical inhibition of USP7 by the small molecule P22077 attenuated PDAC cell growth and induced cell death in vitro and in vivo.
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We subsequently examined the possibility that USP7 inhibition might trigger cell death in canine lymphoma and leukemia cells.
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Furthermore, targeting USP7 contributed to CDDO-Me-induced ovarian cancer cell death, suggesting that USP7 is a novel drug target in ovarian cancer cells.
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Our study demonstrates that loss of HAUSP in colorectal cancer cells potentiates cell death by apoptosis after exposure to various HDAC inhibitors, thus suggesting the potential of a combination of HDAC1 and HAUSP inhibitors as an effective cancer therapy.
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For instance, the loss of HAUSP in colorectal cancer cells potentiates apoptotic cell death by inducing proteasomal degradation of DNMT1, further compounding the potential of HAUSP inhibition as an effective anti-cancer therapy XREF_BIBR - XREF_BIBR.
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USP7 activates cell death.
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USP7 activates cell death. 5 / 6
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In this paper, we demonstrate that inhibition of deubiquitinylase USP7 significantly reduces cell proliferation in vitro and in vivo, blocks DNA replication progression and increases cell death in AML.
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Interestingly, the addition of SCH900776 in P22077 and cytarabine-treated cells did not increase cell death, which suggests that P22077induced cell death is mediated by the USP7/CHK1 axis.
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USP7 silencing in HL-60 cells significantly reduced cell proliferation by increasing apoptotic cell death and the proportion of cells in the G1 phase.
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Like USP7 inhibition, forcing PTEN to the nucleus is sufficient to induce apoptosis in CLL cells, thus strongly suggesting that apoptotic cell death caused by USP7 inhibition is mediated by reactivation of the nuclear pro apoptotic function of PTEN [XREF_BIBR], and that PTEN exerts tumor suppressive functions mostly from the nucleus in CLL.
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The USP7 Inhibitor P5091 Induces Cell Death in Ovarian Cancers with Different P53 Status.
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USP7 affects UHRF1
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USP7 inhibits UHRF1.
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USP7 inhibits UHRF1. 3 / 7
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USP7 prevents UHRF1 from autoubiquitinylation in vitro and regulates its stability in vivo.
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However, active USP7 completely abolished the autoubiquitinylation of UHRF1 by removal of ubiquitin adducts.
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Second, we hypothesize that HAUSP directly inhibits the E3 ubiquitin ligase activity of UHRF1.
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Modified USP7 inhibits UHRF1. 1 / 1
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Overexpression of USP7 partially, but significantly attenuated ursolic acid induced cell death as well as downregulation of MDM2, UHRF1 and DNMT1.
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USP7 activates UHRF1.
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USP7 activates UHRF1. 4 / 5
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We further showed that down-regulation of UHRF1 promoted cell cycle arrest and apoptosis, and overexpression of HPV E6/E7 induced ubiquitin specific protease 7 (USP7), which promoted UHRF1 function, leading to TXNIP inhibition.
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Thus , we predicted that the HPV E6 / E7 oncoproteins might induce expression of USP7 , which in turn , promotes UHRF1 activity and consequently , down-regulates TXNIP expression .
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However, TQ induced HAUSP and UHRF1 deregulation needs further investigation to decipher the molecular events involved, namely the HAUSP down-regulation, which triggers UHRF1 down-regulation followed by apoptosis.
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Taken together, these data indicate that USP7 stabilizes UHRF1 protein levels in vivo and suggest that USP7 removes ubiquitin adducts from UHRF1 and therefore prevents proteasomal degradation of UHRF1.
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USP7 increases the amount of UHRF1.
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Modified USP7 increases the amount of UHRF1. 1 / 1
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Overexpression of HAUSP increased UHRF1 level while HAUSP downregulation induced UHRF1 ubiquitination causing its degradation via a proteasome dependent process [XREF_BIBR].
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USP7 increases the amount of UHRF1. 1 / 1
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It has been reported that the herpes virus associated ubiquitin specific protease HAUSP (or USP7) stabilizes UHRF1 and that knockdown of HAUSP decreases UHRF1 protein levels.
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USP7 affects CD274
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USP7 activates CD274.
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USP7 activates CD274. 8 / 8
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As USP7 abrogation can decrease the expression of PD-L1 without impacting on its mRNA level , and PD-L1 was reported to be ubiquitinated and subjected to proteasome mediated degradation33 ,39 , whether USP7 erases the ubiquitination of PD-L1 needs to be answered .
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Abrogation of USP7 downregulated PD-L1 expression by increasing PD-L1 polyubiquitination .
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As PD-L1 on membrane of cancer cells exhibits immunosuppressive effect through binding to PD-1 on activated T cells XREF_BIBR, whether USP7 positively regulates membrane PD-L1 remains unclear.
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Collectively , our findings indicate that in addition to inhibiting cancer cells proliferation , USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously .
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Inhibition of USP7 decreased PD-L1 expression in vivo The results from in vitro analysis prompted us to make a hypothesis that knockdown of USP7 can affect mPD-L1 expression in vivo , we assessed the ability of USP7-depleted cells to impair tumor growth in BALB / c mice bearing MFC Con and USP7 KD cells .
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Moreover , USP7 can promote the amount of PD-L1 in a dose-dependent manner ( Fig. 3D ) .
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These results demonstrate that abrogation of USP7 can attenuate the PD-L1 / PD-1 interaction and sensitize gastric cancer cells to T cell killing .
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3.6 Inhibition of USP7 decreased PD-L1 expression invivo.
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USP7 bound to CD274 activates CD274. 1 / 1
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Similarly, treatment of MFC cells with mUSP7-sgRNA-lentivirus or Almac4 also led to similar results which further confirm the results derived from XREF_FIG G and H. All these results indicate that USP7 interacts with PD-L1 and deubiquitinates PD-L1 to promote the stability of PD-L1.
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USP7 decreases the amount of CD274.
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USP7 decreases the amount of CD274. 3 / 3
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As USP7 expression was positively correlated with PD-L1 expression in human GC tissues and abrogation of USP7 decreased the expression of PD-L1 in different GC cell lines, we next asked how USP7 regulates the PD-L1 expression.
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As USP7 abrogation can decrease the expression of PD-L1 without impacting on its mRNA level, and PD-L1 was reported to be ubiquitinated and subjected to proteasome mediated degradation XREF_BIBR, XREF_BIBR, whether USP7 erases the ubiquitination of PD-L1 needs to be answered.
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All these results indicate that USP7 abrogation can decrease the expression level of PD-L1 in GC cells.
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USP7 increases the amount of CD274.
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USP7 increases the amount of CD274. 2 / 2
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Moreover, USP7 can promote the amount of PD-L1 in a dose dependent manner (XREF_FIG D).
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3.2 Inhibition of USP7 decreased PD-L1 expression in GC cells.
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ECT2 affects USP7
| 1 1 12
ECT2 activates USP7.
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ECT2 activates USP7. 7 / 7
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ECT2 promotes USP7 intermolecular self-association , - deubiquitination and - stabilization Since ECT2 could not allosterically activate USP7 and it possesses neither E3 ligase nor deubiquitinase activity , we hypothesized that ECT2-promoted USP7 stabilization is likely through enhancing the association of USP7 with other deubiquitinase ( s ) or protecting it from ubiquitination by E3 ligase ( s ) .
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These results indicated that USP7 targets ECT2 for deubiquitination, indicating that ECT2 is a bona fide substrate of USP7.
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Since ECT2 could not allosterically activate USP7 and it possesses neither E3 ligase nor deubiquitinase activity, we hypothesized that ECT2 promoted USP7 stabilization is likely through enhancing the association of USP7 with other deubiquitinase (s) or protecting it from ubiquitination by E3 ligase (s).
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Since ECT2 could not allosterically activate USP7 and it possesses neither E3 ligase nor deubiquitinase activity, we hypothesized that ECT2-promoted USP7 stabilization is likely through enhancing the association of USP7 with other deubiquitinase(s) or protecting it from ubiquitination by E3 ligase(s).
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Considering that the association of USP7 with ECT2 also requires the UBL domain, we wondered whether ECT2 could allosterically enhance the deubiquitinase activity of USP7.
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Although ECT2 fails to activate the enzymatic activity of USP7, we surprisingly found that ECT2 depletion resulted in markedly downregulation of several USP7 substrates including PHF8 XREF_BIBR, RNF168 XREF_BIBR, and MDM2 XREF_BIBR at protein, but not mRNA level.
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However, overexpression of ECT2 in USP7 depleted cells, in which the protein level of overexpressed ECT2 was higher than the endogenous one in control cells, failed to rescue USP7 deficiency associated effects.
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ECT2 deubiquitinates USP7.
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ECT2 leads to the deubiquitination of USP7. 5 / 5
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ECT2 antagonizes USP7 polyubiquitination and promotes its stabilization.
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To test whether ECT2 promoted USP7 stabilization is through opposing ubiquitination mediated proteasome degradation, we next examined whether ECT2 functions to antagonize USP7 ubiquitination.
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Surprisingly, we uncovered that ECT2 promotes intermolecular self association and self deubiquitination of USP7.
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Consistent with the results from in vivo deubiquitination assay, in vitro deubiquitination assay with Sf9 cells purified USP7 and His Ub conjugated USP7 and C223S purified from HeLa cells by high salt and denature buffer demonstrated that ECT2 addition markedly promoted USP7 self deubiquitination.
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Furthermore, we revealed that ECT2 and GEF mt promotes USP7 deubiquitination as efficiently as ECT2/wt does.
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ECT2 inhibits USP7.
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ECT2 inhibits USP7. 1 / 1
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Furthermore, we revealed that ECT2 depletion impaired the upregulation of endogenous USP7 induced by forced expression of GFP-USP7.
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ECT2 increases the amount of USP7.
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Modified ECT2 increases the amount of USP7. 1 / 1
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Western blotting analysis revealed that gain of expression of ECT2 was able to restore the expression of USP7 in ECT2 deficient cells.
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USP7 affects NFkappaB
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USP7 inhibits NFkappaB.
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USP7 inhibits NFkappaB. 5 / 5
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USP31 and USP7 also inhibit NF-kappaB signaling by deubiquitinating K63-linked polyubiquitin chains [ 38,39 ] .
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USP31 and USP7 also inhibit NF-kappaB signaling by deubiquitinating K63 linked polyubiquitin chains [XREF_BIBR, XREF_BIBR].
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We also characterized the inhibitory function of USP7 in the TNFalpha activated NF-kappaB signal pathway.
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In summary, our study uncovers the suppressive mechanisms of HSCARG and USP7 in the TNFalpha activated NF-kappaB signaling pathway.
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41 Here we demonstrated the suppressive role of USP7 in the TNFalpha activated NF-kappaB signaling pathway.
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USP7 bound to IKBKG inhibits NFkappaB. 1 / 1
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In the presence of ICP0, however, it interacts with ICP0 and translocates to the cytoplasm where USP7 binds and deubiquitinates TRAF6 and IKKgamma, thereby inhibiting NF-kappaB and MAPK activation.
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USP7 bound to TRAF6 inhibits NFkappaB. 1 / 1
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In the presence of ICP0, however, it interacts with ICP0 and translocates to the cytoplasm where USP7 binds and deubiquitinates TRAF6 and IKKgamma, thereby inhibiting NF-kappaB and MAPK activation.
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USP7 activates NFkappaB.
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USP7 activates NFkappaB. 6 / 6
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Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing IotakappaBetaalpha and blocking the NF-kappaB pathway.
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We previously demonstrated that the inhibition of USP7 leads to the inhibition of NF-kB directed transcription of pro-inflammatory cytokines such as Il1b , Tnf , and Il6 , identifying USP7 as a potential therapeutic target in inflammatory disease ( 13 ) .
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Our findings support the notion that USP7 activity could be potentially targeted in a substrate selective manner through the development of noncatalytic inhibitors of this deubiquitinase to abrogate NF-kB activity.
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In the nucleus, USP7 increases NF-kappaB stability by regulating NF-kappab transcriptional activity [XREF_BIBR].
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Several other USP domain DUBs were suggested to act on one or several ubiquitinated proteins in the NF-kappaB activating cascade, including USP4, which may act on TRAF2 and TRAF6 93, 94, and USP7, which enhances NF-kappaB responses by deubiquitinating and stabilising NF-kappaB directly 95.
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Blockade of USP7 enzymatic activity leads to a dramatic increase in the ubiquitination and proteasomal degradation of p65 and profoundly inhibits NF-kappaB transcriptional activity.
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USP7 increases the amount of NFkappaB.
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Surprisingly, USP7 knockdown decreases MDM2, AKT, and NF-kappaB gene expression levels in the T47D cell line, which harbors the p53 mutation.
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USP7 affects PML
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USP7 inhibits PML.
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USP7 inhibits PML. 8 / 8
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Thus, USP7 induces PML degradation by another pathway that does not implicate phosphorylation of PML by CK2 or polyubiquitination by RNF4.
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USP7 silencing restored the number of PML NBs and the level of the PML protein (XREF_FIG), indicating that EBNA1 does not disrupt PML NBs in the absence of USP7.
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CK2 and RNF4 regulators of PML catabolism are dispensable for USP7 mediated PML NB disruption and PML degradation.
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On that note, we have recently shown that USP7 promotes the degradation of PML proteins (whose gene is activated by p53) by a mechanism that is independent of its catalytic activity XREF_BIBR.
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In keeping with these observations, USP7 was subsequently shown to negatively regulate PML proteins (even in the absence of EBV or EBNA1), by a mechanism that is independent of its ubiquitin cleavage activity [XREF_BIBR].
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Overall our results point to a novel model of PML regulation in which USP7 triggers degradation of PML by a mechanism that does not require phosphorylation of PML by CK2 or polyubiquitylation by RNF4.
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47 These reports raise the possibility that HAUSP decreases PML protein accumulation indirectly by upregulating UHRF1 protein abundance.
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USP7 could then promote PML degradation either through its catalytic activity or through recruitment of additional cellular proteins.
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USP7 decreases the amount of PML.
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USP7 decreases the amount of PML. 3 / 3
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Contrary to observations with other targets of USP7, we found that USP7 negatively regulates PML levels and PML-NBs by a mechanism that is independent of its catalytic activity and independent of the previously described PML regulators CK2 and RNF4.
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The observations that USP7 promotes PML ubiquitylation and negatively regulates PML levels were counter intuitive since USP7 generally stabilizes its target proteins by removing their ubiquitin moieties.
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Silencing of USP7 caused an increase in PML levels even in the absence of p53 (XREF_FIG), indicating that the ability of USP7 to modulate PML levels is independent of p53.
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USP7 activates PML.
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USP7 activates PML. 1 / 2
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In this study we explored the possibility that USP7 directly regulates PML.
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USP7 affects SUV39H1
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USP7 increases the amount of SUV39H1.
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USP7 increases the amount of SUV39H1. 6 / 6
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Our present studies establish that USP7 is enriched on p53 target promoters and modulates SUV39H1 and H3K9me3 levels in an MDM2 dependent manner.
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Transient transfection of H1299 or HCT116 p53 -/- cells revealed that exogenous MDM2 expression led to downregulation of exogenous SUV39H1 protein levels, while USP7 co-transfection rescued SUV39H1 ex[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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To investigate whether USP7 modulates SUV39H1 expression levels, we generated HCT116 p53 wt cells stably expressing doxycycline inducible USP7 shRNA.
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Transient transfection of H1299 or HCT116 p53 -/- cells revealed that exogenous MDM2 expression led to downregulation of exogenous SUV39H1 protein levels (XREF_FIG; XREF_SUPPLEMENTARY), while USP7 co-transfection rescued SUV39H1 expression in a dose dependent manner (XREF_FIG).
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Our present studies establish that USP7 is enriched on p53 target promoters and modulates SUV39H1 and H3K9me3 levels in a MDM2 dependent manner.
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The present studies define a role of USP7 in the regulation of MDM2 mediated SUV39H1 degradation and maintenance of the H3K9me3 repressive chromatin conformation on p53 target promoters in unstressed [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Modified USP7 increases the amount of SUV39H1. 2 / 2
| 2
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Further, overexpression of USP7 enhanced the endogenous study-state levels of SUV39H1 only in control cells, but not in the cells in which MDM2 was pre-silenced.
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Further, overexpression of USP7 enhanced the endogenous study-state levels of SUV39H1 only in control cells, but not in the cells in which MDM2 was pre-silenced (XREF_SUPPLEMENTARY).
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USP7 activates SUV39H1.
| 4
USP7 activates SUV39H1. 4 / 4
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Finally, we transiently overexpressed USP7 in HCT116 p53 -/- cells, treated with cycloheximide to block new protein synthesis and observed a significant increase in SUV39H1 half-life (XREF_FIG), confirming that USP7 positively regulates SUV39H1 protein stability.
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These results argue that functional USP7 is required to maintain SUV39H1 dependent H3K9me3 enrichment on p53 target promoters.Next, we sought to determine the functional significance of USP7 mediated [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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By either mechanism, our results establish that USP7 modulates the repressive H3K9me3 mark by protecting SUV39H1 from MDM2 mediated degradation and blocking aberrant p53 transactivation of target genes in unstressed p53 wt cells.
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USP7 enhances SUV39H1 stability, independent of p53.
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USP7 inhibits SUV39H1.
| 1
USP7 inhibits SUV39H1. 1 / 1
| 1
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All of these results argue that USP7 regulates SUV39H1 steady-state protein levels and that downregulation of USP7 mimics downregulation of SUV39H1, leading to abrogation of the H3K9me3 mark and trans[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
26971997
USP7 affects Neoplasm Metastasis
| 1 10
USP7 activates Neoplasm Metastasis. 10 / 12
| 1 10
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Through clinical investigation, we detected that USP7 was significantly associated with positive lymph node metastasis, which indicated that USP7 may promote EOC metastasis.
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Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway.
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Pharmacological inhibition of USP7 suppresses growth and metastasis of melanoma cells in vitro and in vivo.
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Overall, USP7 overexpression could promote OS cell metastasis by activating the Wnt and beta-catenin signalling pathway by inducing EMT, suggesting that USP7 is a potential therapeutic target for OS.
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Both of USP7 and cyclin A2 synergistically promote the proliferation and metastasis of HCC cells, reducing intracellular DNA damage.
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In HCC patients with high body fat percentages, the expression of circ-DB is upregulated, and circ-DB downregulates the expression of miR-34a by acting as a miRNA sponge, thus activating USP7, which can promote tumor growth and metastasis by reducing the ubiquitination of Cyclin A2 and many other proteins 68.
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CARM1 and USP7 dependent LSD1 stabilization promotes invasion and metastasis of breast cancer cells [XREF_BIBR].
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In HCC patients with high body fat percentages , the expression of circ-DB is upregulated , and circ-DB downregulates the expression of miR-34a by acting as a miRNA sponge , thus activating USP7 , which can promote tumor growth and metastasis by reducing the ubiquitination of Cyclin A2 and many other proteins68 .
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Moreover, USP7 expression was increased in patients with tumour-node-metastasis (TNM) stages III-IV, poor pathological grade, and positive lymph node metastasis.
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Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF-1alpha to increase its stability, induce epithelial-mesenchymal transition and promote metastasis.
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ICP0 affects USP7
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ICP0 inhibits USP7.
| 8
ICP0 inhibits USP7. 8 / 8
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For example, ICP0 was reported to interact with and degrade USP7, which is a deubiquitylating enzyme like USP9X, but one that promotes HSV-1 replication by reversing ICP0 self ubiquitination [XREF_BIBR, XREF_BIBR].
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It is noteworthy that the synthesis of both negative-and plus-strand coronavirus RNA requires ongoing viral protein production (Kim et al., 1995; Perlman et al., 1986; Sawicki and Sawicki, 1986) , and it is conceivable that concomitant deubiquitination by SARS-CoV PLpro protects replicase subunits against proteasomal degradation.Prompted by the known interaction of ICP0 with cellular USP7, Ploegh and coworkers made use of the active-site directed probe HAUbVME, mentioned above, to monitor DUB activity in lysates of primary fibroblasts infected with HSV-1 .
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Taken together, these data indicate that ICP0 can interact with and promote the proteasome dependent degradation of both USP7 and USP7 beta during HSV-1 infection.ICP0 belongs to the RING-finger class[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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ICP0 Directs the Degradation of USP7, a Mediator of Intrinsic and Innate Immunity.
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ICP0 also disrupts NF-kappaB activation by subverting the activity of the cellular deubiquitylating enzyme USP7.
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It is noteworthy that the synthesis of both negative- and plus-strand coronavirus RNA requires ongoing viral protein production (Kim et al., 1995, Perlman et al., 1986, Sawicki and Sawicki, 1986), and it is conceivable that concomitant deubiquitination by SARS-CoV PLpro protects replicase subunits against proteasomal degradation.Prompted by the known interaction of ICP0 with cellular USP7, Ploegh and coworkers made use of the active-site directed probe HAUbVME, mentioned above, to monitor DUB activity in lysates of primary fibroblasts infected with HSV-1 (Kattenhorn et al., 2005).
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Conversely ICP0 induces the degradation of USP7 [XREF_BIBR].
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The fundamental conclusion of these studies is that depletion of USP7 destabilized ICP0, that ICP0 mediated the degradation of USP7, and that amino acid substitutions in ICP0 that abolished binding to USP7 significantly impaired the ability of HSV-1 to replicate.
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ICP0 increases the amount of USP7.
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ICP0 increases the amount of USP7. 1 / 1
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These results suggests that reductions in USP7 levels mediated by ICP0 may alter chromatinization of the viral genome by destabilizing PRC and REST levels to promote gene expression and reactivation, which is regulated by ICP0 phosphorylation.
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ICP0 deubiquitinates USP7.
| 1
ICP0 leads to the deubiquitination of USP7. 1 / 1
| 1
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These data suggest that ICP0 can promote the ubiquitination and proteasome dependent degradation of both USP7 and USP7 beta during HSV-1 infection.Although the exact identity of USP7 beta still remain[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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ICP0 decreases the amount of USP7.
| 1
ICP0 decreases the amount of USP7. 1 / 1
| 1
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Taken together, these data suggest that ICP0 can recruit both USP7 and USP7 beta during HSV-1 infection and that ICP0 utilises the same USP7 binding domain to interact independently with both isoforms[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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ICP0 activates USP7.
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ICP0 activates USP7. 1 / 1
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In the course of these studies we found and report here that ICP0 also targets USP7 for ubiquitination and proteasome dependent degradation.
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USP7 affects Cell Survival
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USP7 activates Cell Survival. 10 / 11
| 1 9
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USP7 inhibition decreases cell viability.
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By overexpressing PLK1, USP7 that had been depleted by RNAi ceased to induce chromosome misalignment in mitosis and again supported cell proliferation and cell survival.
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USP7 promotes MM cell survival by deubiquitinating Maf proteins , including c-Maf , MafA , and MafB , which are critical transcription factors in myelomagenesis .
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XREF_FIG, USP7 inhibition with P22077 significantly reduced cell viability in three different primary AML samples, while PBMCs were barely affected by the treatment.
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These findings demonstrated that USP7 can positively regulate the OC cell viability.
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The deubiquitinase USP7 stabilizes Maf proteins to promote myeloma cell survival.
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Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway.
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USP7 promoted myeloma cell survival, and when it was inhibited by its specific inhibitor P5091, myeloma cell lines underwent apoptosis.
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XREF_BIBR - XREF_BIBR Targeted by various viral proteins, USP7 can promote cell survival and viral infection, living up to its original name of herpesvirus associated USP.
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As shown in Fig. 2a, USP7 inhibition with P22077 significantly reduced cell viability in three different primary AML samples, while PBMCs were barely affected by the treatment.
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USP7 affects CLSPN
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USP7 activates CLSPN.
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USP7 activates CLSPN. 3 / 6
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USP7 counteracts SCFbetaTrCP- but not APCCdh1 mediated proteolysis of Claspin.
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All of these compounds were shown to abrogate the effects of Usp7 on p53, they also inhibit the enhanced tumourigenicity of claspin caused by Usp7 activity and increase apoptosis in cancer cells [XREF_BIBR].
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USP7 targets Claspin, another damage response mediator protein, to prevent its degradation.
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USP7 inhibits CLSPN.
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USP7 inhibits CLSPN. 1 / 3
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Hence, increased activity of USP7 interferes with the cellular ability to timely degrade Claspin and inactivate Chk1 upon checkpoint termination.
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USP7 increases the amount of CLSPN.
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Modified USP7 increases the amount of CLSPN. 1 / 1
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Unlike inactivation of APC Cdh1, expression of ectopic USP7 WT did not restore Claspin expression in G1 (XREF_FIG), which indicates that the stabilization of Claspin observed in these cells (XREF_FIG) happens outside G1 phase.
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USP7 increases the amount of CLSPN. 1 / 1
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However, as would be expected if USP7 was able to reverse SCF betaTrCP -mediated ubiquitylation of Claspin, induction of USP7 WT fully restored Claspin levels to those seen in asynchronous cells (XREF_FIG).
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USP7 affects CHEK1
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USP7 increases the amount of CHEK1.
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USP7 increases the amount of CHEK1. 3 / 3
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Together, these experiments show that genetic or pharmacological inhibition of USP7 decreases CHK1 protein levels in three different leukemic cell lines, independently of p53 status, which demonstrates the role of USP7 deubiquitinase activity on CHK1 stability.To complete our investigation, experiments were performed to test whether the half-life of CHK1 is regulated by USP7 in leukemic cells.
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Together, these experiments show that genetic or pharmacological inhibition of USP7 decreases CHK1 protein levels in three different leukemic cell lines, independently of p53 status, which demonstrates the role of USP7 deubiquitinase activity on CHK1 stability.
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Importantly, wild type, but not catalytic mutant USP7 can deubiquitinate Chk1 in vivo and in vitro, confirming that USP7 directly regulates Chk1 protein levels.
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Modified USP7 increases the amount of CHEK1. 1 / 1
| 1
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Conversely, overexpression of USP7 wild type, but not a catalytic mutant version, elevates Chk1 levels and increases the half-life of Chk1 protein.
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USP7 inhibits CHEK1.
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USP7 inhibits CHEK1. 1 / 3
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Hence, increased activity of USP7 interferes with the cellular ability to timely degrade Claspin and inactivate Chk1 upon checkpoint termination.
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USP7 activates CHEK1.
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USP7 activates CHEK1. 2 / 2
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Conversely, knockdown of USP7 in SUM159-P2 cells reduced CHK1 stability (XREF_FIG and XREF_SUPPLEMENTARY) but not ZEB1 stability (XREF_SUPPLEMENTARY).
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Two E3 ligase complexes, CUL4A and DDB1 and CUL1 and FBXO6, have shown to be responsible for Chk1 polyubiquitination and degradation; whereas deubiquitinases (DUB), USP1 and USP7, have been reported to promote Chk1 stabilization.
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Modified USP7 activates CHEK1. 1 / 1
| 1
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Conversely, overexpression of USP7 wild type, but not a catalytic mutant version, elevates Chk1 levels and increases the half-life of Chk1 protein.
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USP7 decreases the amount of CHEK1.
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USP7 decreases the amount of CHEK1. 1 / 1
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Depletion or inhibition of USP7 leads to lower Chk1 levels.
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USP7 affects cell cycle
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USP7 activates cell cycle.
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USP7 activates cell cycle. 7 / 7
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Further , we found that USP7 inhibitor inhibited tumor proliferation via promoting the stability of P53 in GC and arrested the cell cycle at G2-M phase .
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Our results indicate that inhibition of USP7 leads to a disruption of cell cycle progression , and triggers DNA damage and apoptosis .
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In this study, we demonstrated that loss of USP7 function inhibits cell growth by promoting cell cycle arrest and apoptosis in A375 and B16 cells.
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Concomitantly , USP7 downregulation significantly arrested the cell cycle , increasing the proportion of A375 cells in the G1 phase and decreasing the proportion in the S phase ( Figures 2G , H ) .
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68 On another hand, overexpression of TRIP12 (R SILAC = 1.62) produces inhibition of USP7, which is an ubiquitin specific processing protease whose depletion induce cell cycle arrest at the S phase.
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Taken together, our results suggest that loss of USP7 function inhibits the melanoma cell cycle and promotes cell apoptosis by mediating AMPK and PI3K/Akt/FOXO signaling pathway activity.
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Overexpression of USP7 has been found to result in increased p53 stabilization and therefore increased cell cycle arrest and apoptosis XREF_BIBR.
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USP7 inhibits cell cycle.
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USP7 inhibits cell cycle. 3 / 3
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The following is/are the supplementary data related to this article : 3.5 Abrogation of USP7 suppressed GC cell proliferation and cell cycle progression.
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USP7 inhibition induces cell apoptosis and cell cycle G2/M arrest, and overcomes taxane resistance by inducing the protein degradation of PLK1, resulting in chromosome misalignment in mitosis.
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Concomitantly, USP7 downregulation significantly arrested the cell cycle, increasing the proportion of A375 cells in the G1 phase and decreasing the proportion in the S phase (XREF_FIG).
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USP7 affects autophagy
| 2 8
USP7 activates autophagy.
| 2 6
USP7 activates autophagy. 8 / 8
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Therefore, the obtained data suggested that USP7 could induce osteoblast differentiation and autophagy to ameliorate osteoporosis by increasing KDM6B expression.
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3.5 USP7 promoted osteoblast differentiation and autophagy to ameliorate osteoporosis by increasing KDM6B expression.
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43 In conclusion , our study demonstrated that up-regulation of miR-15b could inhibit the expression of USP7 , which potentially suppress the osteoblast proliferation , differentiation and autophagy to aggravate osteoporosis through inhibition of KDM6B expression ( Figure 7 ) .
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36 Of note, our data revealed that inhibition of proteasome up-regulated expression of USP7 and KDM6B, while increased USP7 expression promoted osteoblast differentiation and autophagy, alleviating osteoporosis.
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36 Of note , our data revealed that inhibition of proteasome up-regulated expression of USP7 and KDM6B , while increased USP7 expression promoted osteoblast differentiation and autophagy , alleviating osteoporosis .
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Thus, these findings support that restoration of USP7 underlies the anti-osteogenic effect of miR-15b by stimulating osteoblast proliferation, differentiation, and autophagy.
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Mechanistically, miR-15 bound and inhibited USP7 expression, while overexpression of USP7 promoted autophagy of osteoblasts.
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43 In conclusion, our study demonstrated that up-regulation of miR-15b could inhibit the expression of USP7, which potentially suppress the osteoblast proliferation, differentiation and autophagy to aggravate osteoporosis through inhibition of KDM6B expression.
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USP7 inhibits autophagy.
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USP7 inhibits autophagy. 2 / 2
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Silencing of KDM6B reversed the promoting effect on autophagy and proliferation induced by overexpression of USP7.
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43 In conclusion, our study demonstrated that up-regulation of miR-15b could inhibit the expression of USP7, which potentially suppress the osteoblast proliferation, differentiation and autophagy to aggravate osteoporosis through inhibition of KDM6B expression.
33434305
USP7 affects PPARG
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USP7 activates PPARG.
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USP7 activates PPARG. 6 / 9
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HAUSP, but not the catalytically inactive HAUSP C223S mutant, increased the stability of both endogenous and exogenous PPARgamma through its deubiquitinating activity.
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HBX 41,108, a specific inhibitor of HAUSP, abolished the increase in PPARgamma stability induced by HAUSP.
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Herpesvirus associated ubiquitin specific protease (HAUSP) modulates peroxisome proliferator activated receptor gamma (PPARgamma) stability through its deubiquitinating activity.
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Quantitative RT-PCR analysis showed that HAUSP increased the transcript levels of PPARgamma target genes in HepG2 cells, resulting in the enhanced uptake of glucose and fatty acids, and vice versa, upon siRNA knockdown of HAUSP.
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Several ubiquitin ligases, such as FBOX9 and Cul4B, and an ubiquitin specific protease (HAUSP) targeting PPARgamma have been identified, and an increase in PPARgamma stability generally promotes PPARgamma activity and adipogenesis XREF_BIBR - XREF_BIBR.
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HAUSP enhanced the transcriptional activity of both exogenous and endogenous PPARgamma in luciferase activity assays.
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USP7 increases the amount of PPARG.
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USP7 increases the amount of PPARG. 1 / 1
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In addition, knockdown of endogenous HAUSP using siRNA decreased PPARgamma protein levels.
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MDM2 affects USP7
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MDM2 activates USP7.
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MDM2 activates USP7. 7 / 7
| 7
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In vitro and in cancer cell lines, p300 mediated acetylation of MDM2 on Lys 182 and Lys 185 enabled HAUSP to bind, presumably deubiquitinate, and stabilize MDM2.
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These findings suggest that p300 mediated MDM2 acetylation within the NLS domain enables HAUSP to be recruited to the acidic domain, leading to deubiquitination of MDM2 (XREF_FIG).
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HAUSP plays pivotal roles in the stability of p53 and MDM2, raising HAUSP as a potential therapeutic target for tuning p53 mediated anti-tumor activity.
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Both USP2 and USP7 and HAUSP target MDM2 and lead to its degradation XREF_BIBR.
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It has been shown that Mdm2 is the primary target of USP7 mediated stabilization.
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P22077 downregulated USP7 targets MDM2, claspin, and Chk1 [XREF_BIBR] and inhibited neuroblastoma growth [XREF_BIBR], and P50429 inhibited HCT116 proliferation [XREF_BIBR, XREF_BIBR].
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Since MDM2 is the preferred target of USP7 under unstressed conditions [XREF_BIBR, XREF_BIBR], then logically, suppression of USP7 should destabilize MDM2.
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MDM2 inhibits USP7.
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MDM2 inhibits USP7. 3 / 3
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As shown in XREF_FIG, both p53 and Mdm2 had decreased half-lives in hausp heterozygote MEF cells (lanes 5-8) compared with that in wild-type MEF cells (lanes 1-4).
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The results indicated that the mRNA level of MDM2, p21, PUMA, TP53INP1, TP53INP2, GDF15, and IGFBP3, is elevated upon knockdown of either ECT2 or USP7, albeit to variable extents, while the expression of TP53 is unchanged.
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Interestingly, the Mdm2 level decreased after depletion of HAUSP (XREF_FIG, lane 6 versus lane 5), consistent with the previous finding that Mdm2 is a substrate of HAUSP, and Mdm2 is destabilized in hausp knockout cells.
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USP7 affects localization
| 10
USP7 activates localization.
| 7
USP7 activates localization. 6 / 6
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Unlike previous USPs, USP7 modulates the localization and conformational structure editing of the well-known tumor suppressors p53 and PTEN.
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For example, the deubiquitylase MATH-33 recently has been reported to stabilize and activate DAF-16 by antagonizing polyubiquitylation, while its mammalian counterpart USP7 and HAUSP inhibits FOXO1 and FOXO4 by decreasing their nuclear localization and transcriptional activity, respectively, by removing monoubiquitin moieties [XREF_BIBR - XREF_BIBR].
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Furthermore, knockout of one USP7 allele in HCT116 cells (USP7 +/-) resulted in impaired CI-M6PR recycling (XREF_FIG), decreased Arp2/3 localization to VPS35 positive endosomes (XREF_FIG and XREF_SUPPLEMENTARY), and decreased F-actin accumulation on VPS35 positive endosomes (XREF_FIG and XREF_SUPPLEMENTARY).
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XREF_BIBR Moreover, USP7 may contribute to cancer by modulating the nuclear localization of PTEN.
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Amongst its substrates, MDM2 and PTEN have been shown to be deubiquitinated by HAUSP to cause the stabilization or change of cellular localization, respectively, leading to tumorigenesis [XREF_BIBR, XREF_BIBR].
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Furthermore, knockout of one USP7 allele in HCT116 cells (USP7 +/-) resulted in impaired CI-M6PR recycling, decreased Arp2/3 localization to VPS35 positive endosomes, and decreased F-actin accumulatio[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7 bound to PPP2 activates localization. 1 / 1
| 1
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In addition, USP7 interacts with the phosphatase PP2A and supports its active localization in the cytoplasm.
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USP7 inhibits localization.
| 3
USP7 inhibits localization. 3 / 3
| 3
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In contrast, USP7 reduced nuclear localization of PTEN in PC3 cells without affecting total PTEN protein levels (XREF_FIG), consistent with previously reported findings 18.
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Unlike normal HeLa cells, showing co-localization of HAUSP and ANXA1 in the nucleus by forming nuclear foci in response to UV, the absence of HAUSP abrogated the nuclear localization of ANXA1.
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From a functional point of view, USP7 inhibition restores PTEN localization in CLL.
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Ubiquitin affects USP7
| 1 8
Ubiquitin inhibits USP7.
| 1 5
Ubiquitin inhibits USP7. 6 / 6
| 1 5
sparser
Substrate Binding Region of USP2 and USP7 USP2 Inhibition by Full-Length Ubiquitin and the C-Terminally Truncated Mutants, Ubiquitin 1-74 and 1-73 Steady-State Kinetic Parameters for the Hydrolysis of AMC Substrates by UCH-L3 and USP2 Inhibition of USP2 Crystallographic Data and Refinement Statistics Data Set Statistics
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Our result indicated the promotion of TRIP12 expression by TSPY1, providing a clue for investigating the potential mechanism underlying ubiquitin mediated degradation of USP7 in future studies.
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A ubiquitin variant expressed in human tumor cell lines binds and inhibits endogenous USP7, thereby enhancing Mdm2 proteasomal turnover and stabilizing p53.
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Moreover, our experiments showed that TSPY1 could decrease the p53 level by facilitating ubiquitin mediated USP7 degradation.
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TSPY1 induces ubiquitin dependent degradation of USP7.
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Because USP7 could stabilize most of the proteins degraded in extract treated with UbVS and ubiquitin, we tested if inactivation of USP7 using the specific inhibitor XL-188 was sufficient to induce degradation of the substrates that we identified.
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Ubiquitin activates USP7.
| 3
Ubiquitin activates USP7. 3 / 3
| 3
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It shows that ubiquitin trapped in the active site of USP7 causes rearrangements of the catalytic triad and the adjacent " switching " loop of USP7.
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Binding of Ub triggers a drastic conformational change in the active site of HAUSP that realigns the catalytic triad for specific catalysis on the C-terminal di-glycine motif of Ub 36.
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Taking these data together, USP7 beta represents a higher MW species of USP7 that shares significant amino acid homology.ICP0 can catalyse the ubiquitination of USP7 (Boutell et al., 2005), suggesting[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7 affects MYCN
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USP7 activates MYCN.
| 4
USP7 activates MYCN. 4 / 8
| 4
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The removal of ubiquitin and subsequent stabilization of N-Myc suggests HAUSP prevents N-Myc degradation.
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HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc.
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Notably, HAUSP was able to stabilize both N-Myc Delta382 -- 464 and N-Myc Delta346 -- 464 but not N-Myc Delta281 -- 464 in the same assay (XREF_FIG), suggesting that direct interaction is required for HAUSP mediated stabilization of N-Myc.
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Therefore, we reasoned that ablation of HAUSP may drive N-Myc proteolysis.
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USP7 increases the amount of MYCN.
| 1
USP7 increases the amount of MYCN. 1 / 1
| 1
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HAUSP knockdown reduced levels of N-Myc but had no obvious impact on c-Myc levels (XREF_FIG); similar results were obtained in native H1299 and human colon cancer HCT116 cell lines (XREF_SUPPLEMENTARY).
27618649
EBNA1 affects USP7
| 2 7
EBNA1 inhibits USP7.
| 2 5
EBNA1 inhibits USP7. 7 / 7
| 2 5
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If the EBNA1-USP7 association competes with binding to these cellular proteins, EBNA1 may effectively sequester USP7 [XREF_BIBR, XREF_BIBR, XREF_BIBR].
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Similar to HSV1's ICP0, EBNA1 binds and inhibits USF7/ HAUSP, promoting p53 degradation by the Mdm2 pathway [27] .
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USP7 silencing caused a significant decrease in transcriptional activation by EBNA1 (P value 0.004) but did not significantly affect transactivation by Delta395-450.
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Hence, inhibition of USP7 by EBNA1 may exhibit selectivity and contribute twofold to p53 destabilization.
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EBNA-1 can also disrupt the host cell 's USP7 assisted stabilization of p53/TP53, thereby preventing the host cell from entering apoptosis, setting the stage for continual viral replication.
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Hence, inhibition of USP7 by EBNA1 may exhibit selectivity and contribute twofold to p53 destabilization.
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EBNA-1 can also disrupt the host cell’s USP7-assisted stabilization of p53/TP53, thereby preventing the host cell from entering apoptosis, setting the stage for continual viral replication (65).
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EBNA1 activates USP7.
| 2
EBNA1 activates USP7. 2 / 2
| 2
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USP7 and HAUSP is a key regulator of p53 and Mdm2 and is targeted by the Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV).
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We show that EBNA1 also increases the occupancy of USP7 at PML NBs and that CK2 and USP7 bind independently and simultaneously to EBNA1 to form a ternary complex.
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USP7 activates transcription, DNA-templated.
| 1 1 6
sparser
The purified TEF1 was able to activate transcription from the TGF-α promoter in an in vitro transcription assay.
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K63 linked polyubiquitination of HAUSP serves as a scaffold to anchor HIF-1alpha, CBP, the mediator complex, and the super and elongation complex to enhance HIF-1alpha-induced gene transcription.
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A study reported that USP7 is critical for target gene transcription , whereby USP7 targeted NF-kappaB p65 for K48-linked deubiquitination , increased the protein stability of p65 , and ultimately led to increased transcription .
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For example, prior studies have shown that knockdown of USP7 prevents rapid inactivation of the anti-proliferative transcription factor, FOXO4, providing a mechanism to impair the pro survival PI3K and Akt pathway that is commonly activated in MM 60.
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In addition, K63 polyubiquitinated HAUSP serves as a scaffold to anchor HIF-1alpha, CBP, the mediator complex, and the super and elongation complex to enhance the gene transcription activity initiated by HIF-1alpha binding to the hypoxia response element in the promoters of HIF-1alpha target genes, including VEGF, Glut1, and Twist1 [XREF_BIBR].
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USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci.
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Modified USP7 activates transcription, DNA-templated. 2 / 2
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Compared with control disc, overexpression of usp7 increased Ci protein levels but not ci transcription in A-compartment cells.
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Compared with control disc (XREF_FIG), overexpression of usp7 increased Ci protein levels but not ci transcription in A-compartment cells (XREF_FIG and XREF_SUPPLEMENTARY).
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Knockdown of USP7 expression consistently reduced the expression levels of signal transducer and activator of transcription (STAT)-1, STAT-2 and selected IFN inducible genes, including IFN induced protein with tetratricopeptide repeats 3, MX dynamin like GTPase 1 and 2 '-5'-oligoadenylate synthetase 1.
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USP7 affects KAT5
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USP7 activates KAT5.
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USP7 activates KAT5. 3 / 4
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TIPping the balance in adipogenesis : USP7 mediated stabilization of Tip60.
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USP7 enhanced Tip60 protein stability, and Tip60 increased the enrichment of H3K27ac on IL-6 and IL-8 promoter region and activated NF-kappaB p65 to increase IL-6 and IL-8 expression.
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We now report that both Tip60 and Foxp3 proteins are subject to ubiquitination and proteasomal degradation, whereas the actions of a deubiquitinating (DUB) enzyme, ubiquitin specific protease, Usp7 (also known as HAUSP), counteract these events and promote Tip60 and Foxp3 stability and, consequently, Treg suppressive function.
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USP7 increases the amount of KAT5.
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USP7 increases the amount of KAT5. 2 / 3
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Whereas USP7 indeed increased the Tip60 expression level and concurrently decreased the amount of ubiquitinated Tip60, ATF3 expression promoted the effects of USP7 on Tip60 expression (XREF_FIG, lanes 3 vs. lane 2, and lane 5 vs. lane 4) and ubiquitination (XREF_SUPPLEMENTARY, lane 3 vs. lane 2), suggesting that ATF3 might promote USP7 mediated deubiqutination of Tip60.
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USP7, a dominant deubiquitinating enzyme in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinates Tip60 both in intact cells and in vitro and increases Tip60 protein levels.
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Modified USP7 increases the amount of KAT5. 1 / 1
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Similarly, inhibition of USP7 activity by P5091 (as evidenced by increased p53 expression 31), or knockdown of USP7 expression by siRNA, almost completely abolished shATF3 mediated downregulation of Tip60 expression (XREF_FIG, lane 4 vs. lane 3).
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USP7 decreases the amount of KAT5.
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USP7 decreases the amount of ubiquitinated KAT5. 1 / 1
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Whereas USP7 indeed increased the Tip60 expression level and concurrently decreased the amount of ubiquitinated Tip60, ATF3 expression promoted the effects of USP7 on Tip60 expression (XREF_FIG, lanes 3 vs. lane 2, and lane 5 vs. lane 4) and ubiquitination (XREF_SUPPLEMENTARY, lane 3 vs. lane 2), suggesting that ATF3 might promote USP7 mediated deubiqutination of Tip60.
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USP7 affects ARMC5
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USP7 increases the amount of ARMC5.
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USP7 increases the amount of ARMC5. 3 / 3
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Given that silencing of USP7 decreased ARMC5 protein expression and the convinced interaction of USP7 with ARMC5, it is highly likely that USP7 serves as an ARMC5 deubiquitinase.
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Furthermore, USP7 knockdown alone abrogated ARMC5 levels and the reduction of ARMC5 caused by USP7 knockdown could be restored by the proteasome inhibitor MG132, suggesting that USP7 maintain the protein levels of ARMC5 by abrogating its proteasomal degradation.
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Silencing of USP7 decreased ARMC5 levels, accompanied by increasing ARMC5 polyubiquitination, whereas overexpression of USP7 but not its mutants increased ARMC5 levels and reversed ARMC5 polyubiquitination.
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USP7 inhibits ARMC5.
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USP7 inhibits ARMC5. 2 / 2
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Given that USP7 could mediate G1/S transition by targeting ARMC5, it is likely that USP7 is participate in the regulation of cell proliferation.
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Interestingly, we found that USP7 knockdown induced down-regulation of ARMC5.
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USP7 decreases the amount of ARMC5.
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USP7 decreases the amount of ARMC5. 2 / 2
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Silencing of USP7 decreased ARMC5 levels, accompanied by increasing ARMC5 polyubiquitination, whereas overexpression of USP7 but not its mutants increased ARMC5 levels and reversed ARMC5 polyubiquitination.
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Conversely, overexpression of USP7, but not its catalytically mutant, reversed ARMC5 ubiquitination levels.
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USP7 activates ARMC5.
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USP7 activates ARMC5. 2 / 2
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Employing the overexpression and knockdown assay indicated that USP7 could greatly increase the steady state of ARMC5 through the ubiquitin-proteasome pathway and regulate ARMC5 ubiquitination.
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We found that USP7 knockdown resulted in decrease in the half-life of ARMC5; however, overexpression USP7 led to increase in the half-life of ARMC5.
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USP7 affects RB1
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USP7 activates RB1. 1 / 8
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The assessment of Rb turnover showed that HAUSP indeed increased the Rb protein half-life.
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USP7 affects BTRC
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USP7 inhibits BTRC. 4 / 8
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Our studies demonstrated that HAUSP stabilizes REST through deubiquitination and antagonizes beta-TrCP in regulating REST at the post-translational level [XREF_BIBR].
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These data demonstrate that HAUSP stabilizes REST through deubiquitination and antagonizes beta-TrCP in regulating REST at post-translational level.
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It demonstrated that HAUSP stabilized REST through deubiquitination and antagonized beta-TrCP in regulating REST at the post-translational level.
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These data demonstrate that HAUSP stabilizes REST through deubiquitylation and antagonizes beta-TrCP in regulating REST at the post-translational level.
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USP7 affects DNA Damage
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USP7 inhibits DNA Damage.
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USP7 inhibits DNA Damage. 4 / 4
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Our results indicate that inhibition of USP7 leads to a disruption of cell cycle progression, and triggers DNA damage and apoptosis.
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3.5 Inhibiting USP7 triggers DNA damage in canine lymphoma and leukemia cell lines.
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Previous results have demonstrated that inhibition of USP7 induces genotoxic stress and DNA damage in chronic lymphocytic leukemia (CLL) cells.
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Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.
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USP7 activates DNA Damage.
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USP7 activates DNA Damage. 4 / 4
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Interestingly, immunofluorescence analysis targeting endogenous HAUSP and ANXA1 in HeLa cells showed nuclear foci formation of both HAUSP and ANXA1 in the nucleus upon UV induced DNA damage (XREF_FIG), suggesting that HAUSP is possibly involved in the ANXA1 mediated damage response in the nucleus.
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BRE mediates CDC25A stabilization after DNA damage by USP7.
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By generating HAUSP knock-down Jurkat cells (HAUSP KD) with a lentiviral shRNA for HAUSP (XREF_FIG), we evaluated the importance of HAUSP in the regulation of ANXA1 upon UV induced DNA damage.
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USP7 deubiquitinase promotes ubiquitin dependent DNA damage signaling by stabilizing RNF168.
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USP7 affects proteolysis
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USP7 activates proteolysis.
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USP7 activates proteolysis. 5 / 5
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Therefore, we reasoned that ablation of HAUSP may drive N-Myc proteolysis.
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As Usp7 is a deubiquitinase and prevents protein degradation, Uhrf1 protein abundance decreased in T cells after treatment with the Usp7 inhibitor (XREF_FIG).
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USP7 as a deubiquitinase sustained PLK1 protein stability via the C223 site, and inversely, USP7 inhibition by P5091 promoted the protein degradation of PLK1 through the ubiquitination-proteasome pathway.
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It has also been shown that the inhibition USP7 and USP2a which are de-ubiquitinases of Hdm2, increases Hdm2 proteolysis and stabilizes p53 levels in multiple myeloma cells enabling the initiation of apoptosis.
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USP7 counteracts SCFbetaTrCP- but not APCCdh1 mediated proteolysis of Claspin.
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USP7 bound to DNMT1 activates proteolysis. 1 / 1
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These results support the hypothesis that acetylation of KG DNMT1 impairs the otherwise stable interaction between DNMT1 and USP7 and therefore allows protein degradation of DNMT1 to occur.
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USP7 inhibits proteolysis.
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USP7 inhibits proteolysis. 2 / 2
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As USP7 was the most efficient DUB in rescuing degradation, we next investigated how broadly USP7 could rescue protein degradation in UbVS and ubiquitin treated extract.
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USP7 broadly rescues protein degradation in UbVS and ubiquitin treated extract.
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USP7 affects NLRP3
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USP7 activates NLRP3.
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USP7 activates NLRP3. 6 / 6
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Inhibition of USP7 and USP47 impairs NLRP3 inflammasome activation in macrophages.
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These data suggest that USP7 overexpression promotes NLRP3 inflammasome activation and pyroptosis by increasing NOX4.
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USP7 Overexpression Promotes Pyroptosis and NLRP3 Inflammasome Activation in Rat Chondrocytes Through Increasing ROS Production.
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It is then possible that this process is regulated by K11 linked ubiquitin chains, yet it is also possible that USP7 and USP47 do not directly target NLRP3 and that an additional regulated protein, upstream of this process, is mediating this effect.
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Moreover, USP7, USP47, and BRCC3 and ABRO can activate the NLRP3 inflammasome.
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These data suggest that USP7 overexpression promotes NLRP3 inflammasome activation and pyroptosis by increasing ROS production.
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USP7 increases the amount of NLRP3.
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USP7 increases the amount of NLRP3. 1 / 1
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The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1beta and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition.
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USP7 decreases the amount of NLRP3.
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USP7 decreases the amount of NLRP3. 1 / 1
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Thus, USP7 regulates NLRP3 inflammasome activation, and chemical inhibition of USP7 by P22077 promotes the ubiquitination level of NLRP3 and blocks inflammasome activation, indicating the multiple roles of USP7.
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USP7 affects CRY1
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USP7 activates CRY1.
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USP7 activates CRY1. 2 / 5
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This observation indicated that Usp7 knockdown decreased the steady state levels of CRY1 and CRY2 proteins.
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Co-expression of USP7 increased the abundance of CRY1 2.6-fold, confirming that USP7 stabilizes CRY1 (XREF_FIG, n = 4 biological replicates, P = 0.001).
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USP7 inhibits CRY1.
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USP7 inhibits CRY1. 1 / 2
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Using cells stably expressing luciferase under a circadian promoter, we observed that activation of AMPK increased the circadian period as expected, inhibition of Hausp also increased period, and combined activation of AMPK and inhibition of Hausp led to a dramatic increase in period, perhaps reflecting synergistic destabilization of nuclear Cry1 (XREF_FIG).
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USP7 increases the amount of CRY1.
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Modified USP7 increases the amount of CRY1. 1 / 1
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The protein levels of Myc-CRY1 and Myc-CRY2 were increased by co-expression of Myc-USP7 in HEK293T/17 cells (XREF_FIG).
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USP7 affects CCDC6
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USP7 increases the amount of CCDC6.
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USP7 increases the amount of CCDC6. 4 / 4
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The targeting of USP7 to reduce CCDC6 levels appears to be useful for the establishment of new therapeutic approaches in cancer treatment [XREF_BIBR - XREF_BIBR], since it could also affect the stability and turnover of the TKs fused to CCDC6.
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Pharmacological inhibition of USP7 downregulates the expression of CCDC6 involved in homologous recombination and results in DNA repair defects that increase the sensitivity of PARP inhibitors.
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Here we show that the knockdown of USP7 reduces the levels of CCDC6 in HCT116 cells and increases their sensitivity to olaparib.
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The CCDC6 levels are modulated by the deubiquitinase USP7.
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USP7 activates CCDC6.
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USP7 activates CCDC6. 3 / 3
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The overexpression of FLAG-HA-USP7 in HeLa and in H460 cells increased the amount of CCDC6 protein.
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The inhibition of USP7 by P5091 accelerated the degradation of CCDC6 versus control in cycloheximide treated L-NET cells in vitro and sensitized the cells to PARP-inhibitors alone and in combination with cisplatinum.
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Furthermore, in in vitro bladder cancer cell system, we observed that the pharmacological inhibition of the USP7 deubiquitinase enhanced CCDC6 degradation, and by altering the DNA repair mechanisms mediated by homologous recombination, sensitized the bladder tumor cells to the cytotoxic effect of PARP-inhibitors.
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USP7 inhibits CCDC6.
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USP7 inhibits CCDC6. 1 / 1
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The inhibition of USP7, using P5091, was assayed in vitro to accelerate CCDC6 turnover in order to sensitize the neuroendocrine cancer cells to PARP-inhibitors, alone or in association with cisplatinum.
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USP7 affects CTNNB1
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USP7 activates CTNNB1.
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USP7 activates CTNNB1. 4 / 4
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USP7 was also shown to promote cancer by stabilizing beta-catenin and inducing signaling regulating cell fate determination and migration via the Wnt pathway [XREF_BIBR].
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23, 24, 25 NSCLC studies have shown that high expression levels of USP5 and USP7 in lung cancer tissue promote lung cancer cell proliferation by stabilizing beta-catenin.
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Overall, USP7 overexpression could promote OS cell metastasis by activating the Wnt and beta-catenin signalling pathway by inducing EMT, suggesting that USP7 is a potential therapeutic target for OS.
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Genetic ablation or pharmacological inhibition of USP7 robustly increases Wnt and beta-catenin signaling in multiple cellular systems.
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USP7 bound to CTNNB1 activates CTNNB1. 1 / 1
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Notably, USP7 can directly bind with beta-catenin to activate the Wnt and beta-catenin signalling pathway and induce epithelial-mesenchymal transition (EMT) of OS cells.
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USP7 inhibits CTNNB1.
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USP7 inhibits CTNNB1. 2 / 2
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USP7 represses Wnt and beta-catenin signaling through stabilization of Axin, which is a part of the destruction complex that inhibits beta-catenin.
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USP7 inhibits Wnt and beta-catenin signaling through promoting stabilization of Axin.
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USP7 increases the amount of CTNNB1.
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USP7 increases the amount of CTNNB1. 1 / 1
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Likewise, depletion of USP12, USP7, or FBXO36 increased total cellular levels of beta-catenin.
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C/VIF1 affects USP7
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C/VIF1 inhibits USP7. 7 / 7
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Hence, vif1 and vif2 peptides significantly suppressing HAUSP DUB enzymatic activity, ultimately leads to p53 mediated anti-cancer activity [XREF_BIBR].
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We then investigated whether the vif1 and vif2 peptides can inhibit HAUSP DUB activity against ubiquitinated substrates through substrate binding competition.
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Consequently, vif1 and vif2 peptides comprehensively suppress HAUSP activity, effectively restore p53 dependent apoptosis in wild-type p53 carrying cancer cells, and suppress tumor growth in mouse xenograft models.
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HAUSP regulates the activities of MDM2 and p53 by deubiquitination, while vif1 and vif2 antagonize HAUSP and promote p53 dependent apoptosis XREF_BIBR.
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They further demonstrated that vif1 and vif2 peptides robustly suppress HAUSP DUB enzymatic activity, ultimately leading to p53 mediated anti-cancer activity [XREF_BIBR].
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2.5.2 Vif1 and vif2 : Peptide inhibitors of HAUSP deubiquitinase (US20140073585A1).
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Comprehensive inhibition of HAUSP deubiquitinase activity by vif1 and vif2 peptides.
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ATM affects USP7
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ATM inhibits USP7.
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ATM inhibits USP7. 3 / 5
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Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.
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CK2 's stabilization of USP7 further contributes to MDM2 stabilization and downregulation of p53, and after ionizing radiation, the ATM dependent protein phosphatase PPM1G downregulates USP7, reversing its effects on MDM2 and p53 [XREF_BIBR].
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ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.
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ATM activates USP7.
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ATM activates USP7. 2 / 2
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The herpesvirus associated ubiquitin specific protease (also named as USP7) can be activated by ATM to stabilize p53 response to DNA damage.
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The herpesvirus-associated ubiquitin-specific protease (also named as USP7) can be activated by ATM to stabilize p53 response to DNA damage. xref , xref However, DNA damage cannot increase the USP15 production to stabilize p53 ( xref ).
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USP7 affects SHH
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USP7 activates SHH.
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USP7 activates SHH. 3 / 3
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The Gli-luciferase reporter assays in NIH3T3 cells and Sufu -/- MEF cells indicated that HAUSP positively regulated Shh pathway downstream of Sufu and at levels of Gli proteins (XREF_FIG).
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The Gli-luciferase reporter assays in NIH 3T3 cells and Sufu -/- MEF cells indicated that HAUSP positively regulated Shh pathway downstream of Sufu and at levels of Gli proteins.
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Usp7 promotes medulloblastoma cell survival and metastasis by activating Shh pathway.
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USP7 inhibits SHH.
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USP7 inhibits SHH. 2 / 2
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Overexpression of HAUSP promoted whereas HAUSP CA decreased Shh pathway activity.
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Overexpression of HAUSP promoted whereas HAUSP CA decreased Shh pathway activity (XREF_FIG).
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USP7 decreases the amount of SHH.
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USP7 decreases the amount of SHH. 2 / 2
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Knockdown of endogenous hausp suppressed the expression of Shh reporter gene and attenuated endogenous Gli levels.
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Knockdown of endogenous hausp suppressed the expression of Shh reporter gene and attenuated endogenous Gli levels (XREF_FIG).
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USP7 affects F_actin
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USP7 increases the amount of F_actin.
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USP7 increases the amount of F_actin. 3 / 3
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Additionally, reconstitution of USP7 +/- cells with USP7 Y143X found in subject # 6 failed to rescue CI-M6PR recycling or rescue Arp2/3 and F-actin levels on FAM21 positive endosomes (XREF_FIG).
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Furthermore, CRISPR and Cas9 knockout of USP7 in hypothalamic neurons resulted in similar phenotypes, including reduced TRIM27 protein levels and diminished the level of F-actin on FAM21 positive endo[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Furthermore, CRISPR and Cas9 knockout of USP7 in hypothalamic neurons resulted in similar phenotypes, including reduced TRIM27 protein levels (XREF_FIG) and diminished the level of F-actin on FAM21 positive endosomes (XREF_FIG).
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USP7 decreases the amount of F_actin.
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USP7 decreases the amount of F_actin. 2 / 2
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Analysis of these cells revealed that knockdown of USP7 in TRIM27 3KR cells significantly increased Arp2/3 and F-actin levels on FAM21 positive endosomes (XREF_FIG).
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Analysis of these cells revealed that knockdown of USP7 in TRIM27 3KR cells significantly increased Arp2/3 and F-actin levels on FAM21 positive endosomes.
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USP7 activates F_actin.
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USP7 activates F_actin. 2 / 2
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Furthermore, knockout of one USP7 allele in HCT116 cells (USP7 +/-) resulted in impaired CI-M6PR recycling (XREF_FIG), decreased Arp2/3 localization to VPS35 positive endosomes (XREF_FIG and XREF_SUPPLEMENTARY), and decreased F-actin accumulation on VPS35 positive endosomes (XREF_FIG and XREF_SUPPLEMENTARY).
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Furthermore, knockout of one USP7 allele in HCT116 cells (USP7 +/-) resulted in impaired CI-M6PR recycling, decreased Arp2/3 localization to VPS35 positive endosomes, and decreased F-actin accumulatio[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7 affects NCL
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USP7 activates NCL.
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USP7 activates NCL. 2 / 2
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Therefore, HAUSP not only prevents nucleolin degradation by the 26S proteasome but also regulates its functions.
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This observation indicates that Mdm2 may recruit nucleolin to HAUSP, and that HAUSP then increases the stability of both Mdm2 and nucleolin via its deubiquitinating enzyme activity.
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USP7 activates ubiquitinated NCL. 1 / 1
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Depletion of HAUSP causes an accumulation of ubiquitinated nucleolin, which is enhanced during the IR response (XREF_FIG).
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USP7 decreases the amount of NCL.
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USP7 decreases the amount of NCL. 1 / 2
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HAUSP knockdown not only reduced HAUSP expression level but also decreased nucleolin level (XREF_FIG).
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USP7 increases the amount of NCL.
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Modified USP7 increases the amount of NCL. 1 / 1
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In addition to the deubiquitinating activity, the dose dependent expression of HAUSP increased nucleolin protein levels (XREF_FIG).
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USP7 increases the amount of NCL. 1 / 1
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HAUSP knockdown not only reduced HAUSP expression level but also decreased nucleolin level (XREF_FIG).
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USP7 affects Proteasome
| 1 2
USP7 inhibits Proteasome.
| 1 1
USP7 inhibits Proteasome. 2 / 4
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Because USP7 broadly rescued substrate degradation in UbVS/ubiquitin-treated extract ( xref , xref ) and has been reported to be associated with the proteasome ( xref ; xref ), USP7 might inhibit the proteasome independent of its catalytic activity, as is known for USP14 ( xref ).
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After in-depth study, we found that USP7 could inhibit the proteasome pathway mediated degradation of Ki-67 protein by its deubiquitination function, and thus stabilize Ki-67 protein in NSCLC cells.
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USP7 activates Proteasome.
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USP7 activates Proteasome. 1 / 2
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Mechanistic studies revealed that arsenic plus BaP co-exposure up-regulates MCL-1 protein levels by synergistically activating the PI3K/Akt/mTOR pathway to increase the level of a deubiquitinase USP7, which in turn reduces the level of MCL-1 protein ubiquitination and prevents its subsequent proteasome degradation.
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USP7 affects Hedgehog
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USP7 activates Hedgehog. 4 / 5
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We next examined whether Usp7 synergizes with GMPS to positively regulate Ci and Hh signaling.
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We next examined whether Usp7 synergizes with GMPS to positively regulate Ci and Hh signaling, Double knockdown of usp7 and gmps caused a more dramatic decrease of ptc-lacZ expression than usp7 or gmps single knockdown (XREF_FIG).
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In sum, Usp7 modulates Ci and Hh signaling through its interaction with Ci and its deubiquitinase activity.
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In sum, Usp7 modulates Ci and Hh signaling through its interaction with Ci and its deubiquitinase activity.We next determined whether Usp7 stabilizes Ci through deubiquitinating Ci using a cell based [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7 bound to GMPS activates Hedgehog. 1 / 1
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Given that both usp7 and gmps are ubiquitously expressed in wing discs, these results suggest that Usp7 most likely form a complex with GMPS to modulate Hh pathway in vivo.The mammal homologs of Ci, G[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7 activates Genomic Instability.
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USP7 activates Genomic Instability. 5 / 5
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We observed that USP7 depletion induced genomic instability that may result from a change in stability of mitotic checkpoint proteins.
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USP7 Depletion Causes Genomic Instability.
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Collectively these data indicates that USP7 depletion causes genomic instability, one of the key hallmarks of cancer [XREF_BIBR].
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Collectively these data indicates that USP7 depletion may cause genomic instability, one of the hallmarks of cancer [XREF_BIBR].
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Here, we found that USP7 depletion causes genomic instability characterized by abnormal chromosomes segregation, accumulation of micronuclei and increased aneuploidy.
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USP7 inhibits Genomic Instability.
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USP7 inhibits Genomic Instability. 1 / 1
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The results presented in this study provide the first evidence that loss of USP7 leads to genomic instability by destabilizing one of the key mitotic checkpoint components.
25003721
USP7 affects EZH2
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USP7 activates EZH2.
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USP7 activates EZH2. 4 / 4
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Herein, we identified that EZH2 is a deubiquitination target of USP7 and that EZH2 protein stability is increased by USP7.
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Moreover, another research illustrated that USP7 elevates EZH2 stability by mediating EZH2 deubiquitination in prostate cancer cells [XREF_BIBR].
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XREF_BIBR Downregulation of USP7 promotes the stabilization of EZH2 protein.
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To further validate our findings, we tested whether USP7 specific inhibitor suppresses USP7 mediated stabilization of EZH2 protein.
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USP7 increases the amount of EZH2.
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Modified USP7 increases the amount of EZH2. 2 / 2
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Overexpression of USP7 promoted the expression of EZH2 protein, but overexpression of a USP7 mutant did not change the EZH2 level.
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Among these three, the EZH2 protein expression was increased the most by USP7 overexpression.
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USP7 affects ERCC6
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USP7 activates ERCC6.
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USP7 activates ERCC6. 5 / 5
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Together UVSSA and USP7 prevent DNA damage induced degradation of CSB, facilitate CSA and CSB dependent ubiquitylation of arrested RNAPIIo (the phosphorylated form of RNAPII during elongation), its re[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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UVSSA and USP7 antagonize proteasomal degradation of CSB at the damage site (XREF_FIG C).
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USP7 targeting XPC and CSB.
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Together UVSSA and USP7 prevent DNA damage induced degradation of CSB, facilitate CSA and CSB dependent ubiquitylation of arrested RNAPIIo (the phosphorylated form of RNAPII during elongation), its remodeling, and USP7 dependent deubiquitylation, and its recycling to non phosphorylated RNAPIIa for transcription initiation.
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Together UVSSA and USP7 prevent DNA damage induced degradation of CSB, facilitate CSA and CSB dependent ubiquitination of arrested RNAPIIo (the phosphorylated form of RNAPII during elongation), its remodeling and USP7 dependent deubiquitination, and its recycling to non phosphorylated RNAPIIa for transcription initiation.
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USP7 decreases the amount of ERCC6.
| 1
USP7 decreases the amount of ERCC6. 1 / 1
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Indeed, depletion of USP7 by siRNA caused a similar RRS deficiency and decreased levels of CSB.
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USP7 affects DNA replication
| 2 4
USP7 activates DNA replication.
| 2 3
USP7 activates DNA replication. 5 / 5
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In this paper, we demonstrate that inhibition of deubiquitinylase USP7 significantly reduces cell proliferation in vitro and in vivo, blocks DNA replication progression and increases cell death in AML.
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USP7 has also recently been shown to promote DNA replication via acting as a DUB for the UBL SUMO 96 .
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Inhibition of USP7 hinders DNA replication by reducing fork velocity and firing of new origins [ 50 ] .
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USP7 targeting by LANA appears to inhibit DNA replication, a phenomenon mirroring the situation reported for the functionally equivalent EBNA1 latency protein of Epstein-Barr virus.
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USP7 has also recently been shown to promote DNA replication via acting as a DUB for the UBL SUMO 96 .
28959952
USP7 inhibits DNA replication.
| 1
USP7 inhibits DNA replication. 1 / 1
| 1
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In this paper, we demonstrate that inhibition of deubiquitinylase USP7 significantly reduces cell proliferation in vitro and in vivo, blocks DNA replication progression and increases cell death in AML.
32447346
TSPY1 affects USP7
| 6
TSPY1 inhibits USP7.
| 3
TSPY1 inhibits USP7. 3 / 3
| 3
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With this work, we reveal that TSPY1 suppresses ubiquitin specific peptidase 7 (USP7)-mediated p53 function; the promotion of spermatogonial proliferation by TSPY1 through the p53 signaling pathway probably contributes to human spermatogenesis.
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These observations suggest that TSPY1 and TSPYL5 can induce USP7 degradation via the 26S proteasome system.
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TSPY1 induces ubiquitin dependent degradation of USP7.
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TSPY1 activates USP7.
| 2
TSPY1 activates USP7. 2 / 2
| 2
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Correspondingly, it is highly possible that the regulation of USP7 mediated p53 function by TSPY1 is an important molecular mechanism underlying its function in human spermatogenesis.
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These findings provide the first evidence that TSPY1, in addition to TSPYL5, can promote the ubiquitin mediated degradation of USP7, suggesting TSPYL5 independent regulation of USP7 mediated p53 function by TSPY1.
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TSPY1 decreases the amount of USP7.
| 1
TSPY1 decreases the amount of USP7. 1 / 1
| 1
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To explore the mechanism underlying downregulation of the USP7 level by TSPY1 and TSPYL5, we treated cells overexpressing TSPY1 and TSPYL5 with a protein biosynthesis inhibitor, cycloheximide (CHX), and observed more obvious degradation of USP7; this effect could be inhibited by MG132 treatment.
29748603
USP7 affects BMI1
1 | 5
USP7 activates BMI1.
| 3
USP7 activates BMI1. 3 / 3
| 3
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Knockdown of USP7 or USP11 causes increased turnover of chromatin bound MEL18 and BMI1, whereas over-expression of the USPs reduces the levels of mono- and poly-ubiquitination of these proteins.
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Importantly, knockdown of either USP7 or USP11 reduces the total and chromatin bound pool of BMI1 and MEL18, and the effects can be mitigated by inhibiting proteasome function.
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Knockdown of USP7 or USP11 causes increased turnover of chromatin bound MEL18 and BMI1, whereas over-expression of the USPs reduces the levels of mono- and poly-ubiquitination of these proteins [XREF_BIBR].
20974139
USP7 increases the amount of BMI1.
1 | 1
USP7 increases the amount of BMI1. 1 / 1
| 1
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We showed that USP7 disruption impairs H2A and ultraviolet radiation (UVR)-induced gammaH2AX monoubiquitination, and decreases the levels of pBmi1, Bmi1, RNF168 and BRCA1.
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Catalytically active USP7 increases the amount of BMI1. 1 / 1
1 |
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Regulation of the stability of the PRC1 complex also appears to be another facet, as the de-ubiquitination of the PRC1 components BMI1 and MEL18 by the ubiquitin-specific proteases 7 and 11 has been shown to increase their abundance (Maertens et al., 2010), whereas the loss of these ubiquitin-specific proteases promotes INK4A transcriptional activation.
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USP7 decreases the amount of BMI1.
| 1
USP7 decreases the amount of BMI1. 1 / 1
| 1
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We showed that USP7 disruption impairs H2A and ultraviolet radiation (UVR)-induced gammaH2AX monoubiquitination, and decreases the levels of pBmi1, Bmi1, RNF168 and BRCA1.
25894431
USP7 affects ANXA1
| 6
USP7 decreases the amount of ANXA1.
| 3
USP7 decreases the amount of ANXA1. 2 / 2
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The result showed that HAUSP could reduce the ANXA1 ubiquitination level more upon UV, possibly due to the increase in HAUSP-ANXA1 binding.
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HAUSP reduced the level of ANXA1; however, a catalytically inactive mutant of HAUSP (C223S) has less effect on the ANXA1 ubiquitination (XREF_FIG), which is different from the fully denatured condition (XREF_FIG).
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Modified USP7 decreases the amount of ANXA1. 1 / 1
| 1
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Overexpression of HAUSP reduced the ubiquitination level of ANXA1 (XREF_FIG).
25695607
USP7 inhibits ANXA1.
| 2
USP7 inhibits ANXA1. 2 / 2
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Overall, our findings demonstrate that depletion of HAUSP can decrease ANXA1 stability and cleavage of ANXA1, thereby reducing not only cell apoptosis upon UV but also transmigration of macrophages mediated by Ac2-26.
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Unlike normal HeLa cells, showing co-localization of HAUSP and ANXA1 in the nucleus by forming nuclear foci in response to UV, the absence of HAUSP abrogated the nuclear localization of ANXA1.
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USP7 increases the amount of ANXA1.
| 1
Modified USP7 increases the amount of ANXA1. 1 / 1
| 1
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Moreover, dose dependent overexpression of HAUSP increased the ANXA1 protein level, as confirmed by western blotting (XREF_SUPPLEMENTARY).
25695607
USP7 affects HIF1A
| 6
USP7 activates HIF1A.
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USP7 activates HIF1A. 2 / 2
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To substantiate the in vivo stabilization of HIF-1alpha by HAUSP, a transient co-transfection experiment showed that overexpression of HAUSP increased HIF-1alpha at the protein levels but not the mRNA levels (XREF_FIG and XREF_SUPPLEMENTARY), and further activated a Twist1 promoter driven reporter construct (XREF_FIG) XREF_BIBR.
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Finally, co-immunoprecipitation experiments using anti-HIF-1alpha antibodies to pull down VHL and components of the E3 ubiquitin ligase complex showed that HAUSP knockdown did not affect the interaction between HIF-1alpha and VHL or the components of the E3 ubiquitin complex (XREF_SUPPLEMENTARY), indicating that the ability of HAUSP to increase HIF-1alpha stability was independent of its interaction with VHL or the components of the E3 ubiquitin ligase complex.
27934968
USP7 decreases the amount of HIF1A.
| 2
USP7 decreases the amount of ubiquitinated HIF1A. 1 / 1
| 1
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In vivo deubiquitination assays showed that only wild-type HAUSP significantly decreased the polyubiquitinated HIF-1alpha levels (XREF_SUPPLEMENTARY).
27934968
USP7 decreases the amount of HIF1A. 1 / 1
| 1
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Knockdown of HAUSP in PC3 cells lowered the endogenous HIF-1alpha levels, but not the endogenous HIF-1alpha mRNA levels, induced by hypoxia and abolished hypoxia triggered EMT and the in vitro migration and invasion activities (XREF_SUPPLEMENTARY).
27934968
USP7 inhibits HIF1A.
| 1
USP7 inhibits ubiquitinated HIF1A. 1 / 1
| 1
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Wild-type HAUSP, but not the enzymatically inactive mutant (HAUSP-CS) XREF_BIBR, decreased the ubiquitinated HIF-1alpha in vivo under MG132 treatment (XREF_SUPPLEMENTARY).
27934968
USP7 increases the amount of HIF1A.
| 1
USP7 increases the amount of ubiquitinated HIF1A. 1 / 1
| 1
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Knockdown of HAUSP in H1299 cells increased the polyubiquitinated HIF-1alpha levels (XREF_SUPPLEMENTARY).
27934968
VIRF-2 affects USP7
| 5
VIRF-2 activates USP7. 5 / 5
| 5
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The present finding of USP7 targeting by vIRF-2, in addition to interactions of HHV-8 vIRFs 1, 3, and 4 with the deubiquitinase, is intriguing, especially as the biological consequences of these interactions appear to be somewhat contradictory and counterintuitive.
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The specific identification of TRAF3 and TRAF6 regulation via vIRF-2 targeting of USP7 represents a novel mechanism of viral protein activity via USP7 interaction.
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The presented data are the first to identify vIRF-2 targeting of USP7 and its role in HHV-8 biology, expanding our understanding of the repertoire and importance of virus-host interactions.
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Here, we report that vIRF-2 also interacts with USP7, via a means distinguishable from USP7 interactions with other vIRFs and other proteins, that this interaction modulates antiviral signaling via disruption of USP7 interactions with innate immune signaling proteins TRAF3 and TRAF6, and that vIRF-2 targeting of USP7 regulates HHV-8 productive replication.
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To determine the influence of vIRF-2 targeting of USP7 on TRAF3 and TRAF6 polyubiquitination in the context of infection, we compared the ubiquitination status of these TRAFs, expressed in tagged form from lentiviral vectors, in lytically reactivated iSLK cells infected with wild-type or vIRF-2.
31666375
Cycloheximide affects USP7
| 5
Cycloheximide activates USP7. 5 / 5
| 5
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The stabilizing effect of USP7 upon E1B-55K was further supported by cycloheximide chase assays demonstrating a reduced half-life of E1B-55K in the USP7 knockdown background (XREF_SUPPLEMENTARY) and after HBX or HBX41108 treatment (XREF_SUPPLEMENTARY).
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Finally, we transiently overexpressed USP7 in HCT116 p53 -/- cells, treated with cycloheximide to block new protein synthesis, and observed a significant increase in SUV39H1 half-life, confirming that[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Moreover, control or USP7 knockdown cells were treated with cycloheximide (CHX), and endogenous MLL5 protein levels evaluated for the indicated times.
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Finally, we transiently overexpressed USP7 in HCT116 p53 -/- cells, treated with cycloheximide to block new protein synthesis and observed a significant increase in SUV39H1 half-life (XREF_FIG), confirming that USP7 positively regulates SUV39H1 protein stability.
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Cells were overexpressed for KDM6B and USP7 expression and were treated with 50mug/mL cycloheximide.
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USP7 affects Neoplasms
| 4
USP7 activates Neoplasms. 4 / 5
| 4
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Moreover , USP7 promotes tumor progression by deubiquitinating and stabilizing the histone demethylase PHF8 and by upregulating cyclin A2 in breast cancer ( Wang et al. 2016 ) .
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USP7 was also shown to promote cancer by stabilizing beta-catenin and inducing signaling regulating cell fate determination and migration via the Wnt pathway [ 107 ] .
| PMC
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A high USP7 expression may promote cancer progression and predict unfavourable prognosis of cancer patients , especially those with EOC .
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Further , we found that USP7 inhibitor inhibited tumor proliferation via promoting the stability of P53 in GC and arrested the cell cycle at G2-M phase .
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USP7 affects ECT2
| 1 4
USP7 activates ECT2. 5 / 5
| 1 4
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To further support this deduction, the potential of USP7 to modulate the steady-state level of ECT2 protein was assessed by cycloheximide (CHX) chase assays.
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To gain molecular insights into the functional connection between USP7 and ECT2, we examined whether USP7 promoted ECT2 stabilization is dependent on its ubiquitin specific protease activity.
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Consistent with the observation that enzymatic inhibition of USP7 resulted in ECT2 destabilization , treatment of HeLa cells with USP7 inhibitor GNE-6640 for 4 h resulted in a marked increase in the level of ubiquitinated ECT2 species and a decrease of total ECT2 ( Figure 5J and S4C ) .
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Given that ECT2 is an ubiquitinated protein XREF_BIBR, XREF_BIBR and USP7 promotes the stabilization of ECT2, we next asked the question whether USP7 functions to deubiquitinate ECT2.
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These results indicated that USP7 targets ECT2 for deubiquitination, indicating that ECT2 is a bona fide substrate of USP7.
32929379
USP7 affects EBNA1
| 5
USP7 activates EBNA1. 5 / 5
| 5
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However we have also shown that USP7 can stimulate the assembly of EBNA1 on oriP elements in transfected plasmids suggesting that USP7 might play a role in the initial association of EBNA1 with these elements upon initial EBV infection, and/or during the switch from the EBV latency form in nonproliferating cells, in which EBNA1 is not expressed, to latency forms in proliferating cells in which EBNA1 is expressed and bound to oriP.
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Therefore we conclude that USP7 can stimulate the assembly of EBNA1 on oriP elements in vivo.
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USP7 also contributes to EBNA1 mediated transcriptional activation and stimulates the assembly of EBNA1 on oriP elements in transfected plasmids [XREF_BIBR].
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While stoichiometric amounts of USP7 were sufficient to stimulate the DNA binding activity of EBNA1, only at higher USP7 concentrations was USP7 observed to be stably associated with the EBNA1 and DNA complex in vitro.
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In keeping with this hypothesis, we found that USP7 within this complex can mediate an interaction with GMPS which promotes deubiquitylation of histone H2B and that USP7 contributes to EBNA1 mediated transcriptional activation.
19834552
USP7 activates reactive oxygen species.
| 2 2
USP7 activates reactive oxygen species. 4 / 4
| 2 2
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Flow cytometry results showed that USP7 overexpression induced pyroptosis and ROS production which was blocked by apocynin (XREF_FIG).
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ROS assay showed that H 2 O 2 elevated ROS production which was abolished by USP7 KD or USP7 inhibition (XREF_FIG).
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These data suggest that H2O2 induced ROS production , NLRP3 inflammasome activation , and pyroptosis by increasing USP7 .
33584299
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ROS assay showed that H2O2 elevated ROS production which was abolished by USP7 KD or USP7 inhibition ( Figure 2B ) .
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ROS assay showed that H 2 O 2 elevated ROS production which was abolished by USP7 KD or USP7 inhibition (XREF_FIG).
33584299
USP7 affects methylation
| 5
USP7 inhibits methylation.
| 3
USP7 inhibits methylation. 3 / 3
| 3
eidos
Mechanistic study demonstrated that USP7 suppresses DNMT1 recruitment and DNA methylation through its deubiquitinase activity and the interaction with DNMT1 .
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Thus , USP7 not only plays a role in stabilizing DNMT1 and UHRF1 , but also serves to suppress excessive DNA methylation by DNMT1 .
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Both physical interaction with DNMT1 and deubiquitinase activity are required for USP7 to inhibit DNMT1 replication fork association and DNA methylation in USP7-KO cells .
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USP7 activates methylation.
| 2
USP7 activates methylation. 2 / 2
| 2
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Felle et al. showed that USP7 stimulated both maintenance and de novo methylation activity of DNMT1 in vitro39 , and knockdown of USP7 reduced DNA methylation in three silenced genes , although whether USP7 knockdown affected global DNA methylation was not analyzed .
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In addition , it is formally possible that USP7 stimulates DNA methylation at a fraction of genomic regions , although overall it suppresses global DNA methylation .
32884836
USP7 affects cell migration
| 1 4
USP7 activates cell migration.
| 1 2
USP7 activates cell migration. 3 / 3
| 1 2
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USP7 promotes cell migration , invasion , and sphere formation in part through EZH2 stabilization In prostate cancer , USP7 overexpression has been reported to show a direct correlation with tumor aggressiveness ( Song et al ., 2008 ) .
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The migration capacity of HCC cells was also tested by wound healing assay, revealing that USP7 can promote tumor cell migration (XREF_FIG).
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Next, biological function assays demonstrated that USP7 knockdown markedly inhibited OS cell migration and invasion, whereas USP7 overexpression enhanced it.
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USP7 inhibits cell migration.
| 2
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Consistently, downregulation of USP7 inhibited cell migration and invasion in cancer.
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Furthermore, the USP7 specific inhibitor P5091 augmented the inhibition of cell migration, invasion, and sphere forming abilities by EZH2 inhibitors in prostate cancer cells.
32453339
USP7 affects FOXO
| 1 4
USP7 inhibits FOXO.
| 1 2
USP7 inhibits FOXO. 3 / 3
| 1 2
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However, USP7 does negatively regulate FOXO transcriptional activity towards endogenous promoters.
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While USP7 inhibits Foxo through deubiquitination it has no effect on protein levels of Foxo reinforcing the view that monoubiquitination of Foxo acts independent of protein degradation.
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While USP7 inhibits Foxo through deubiquitination it has no effect on protein levels of Foxo reinforcing the view that monoubiquitination of Foxo acts independent of protein degradation.
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USP7 activates FOXO.
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USP7 activates FOXO. 2 / 2
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Besides, USP7 targets the proteins of the FOXO family in lung cancer and DNMT1 in colon cancer and acts as a deubiquitinase for SUMO (small ubiquitin like modifier) [XREF_BIBR].
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Surprisingly, neither monoubiquitination nor USP7 mediated deubiquitination affects FOXO protein stability.
20429422
USP7 affects E3_Ub_ligase
| 5
USP7 inhibits E3_Ub_ligase.
| 3
USP7 inhibits E3_Ub_ligase. 3 / 3
| 3
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Indeed, HAUSP was shown to reduce the E3 ligase activity (autoubiquitination) of wild-type UHRF1 but not in the UHRF1 K659E mutant, disturbing the UHRF1 domain involved in its interaction with HAUSP [XREF_BIBR].
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Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR).
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Second, we hypothesize that HAUSP directly inhibits the E3 ubiquitin ligase activity of UHRF1.
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USP7 activates E3_Ub_ligase.
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USP7 activates E3_Ub_ligase. 2 / 2
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This result indicates that Usp7 augments the E3 enzymatic activity of RAUL.
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40 HAUSP modulates the stability of three E3 ligases, including RING finger protein 168 (RNF168), 74 to regulate histone H2A and participate in Ub dependent DNA damage signaling.
29967688
DAXX affects USP7
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DAXX activates USP7.
| 2
DAXX activates USP7. 2 / 4
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These findings suggest that Daxx directs HAUSP toward its associated protein MDM2, to increase MDM2 activity towards p53 (Tang, Qu, & Zhang, 2006).
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Deubiquitination by USP7 stabilizes p53 and MDM2, with the adaptor protein Daxx directing USP7 to MDM2.
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DAXX inhibits USP7.
| 1
DAXX inhibits USP7. 1 / 1
| 1
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Strikingly, PML counteracts HAUSP function in regulating PTEN ubiquitinylation and nuclear localization via the adaptor protein DAXX, which inhibits HAUSP mediated deubiquitinylation of PTEN [18].
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Doxorubicin affects USP7
2 | 3
Doxorubicin inhibits USP7.
| 2
Doxorubicin inhibits USP7. 2 / 2
| 2
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Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8 mice.
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Doxorubicin reduced SIRT1 deacetylase activity, and elevated proteasomal activity and USP7; it also increased the protein level of p300 and ubiquitinated proteins in hearts from aged SAMP8.
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Doxorubicin increases the amount of USP7.
2 |
Doxorubicin increases the amount of USP7. 2 / 2
2 |
ctd
No evidence text available
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No evidence text available
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Doxorubicin activates USP7.
| 1
Doxorubicin activates USP7. 1 / 1
| 1
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Doxorubicin induced functional deteriorations and elevations of USP7 related apoptotic and catabolic signalling in the senescent heart Resveratrol protects against doxorubicin induced alterations through the restoration of SIRT1 deacetylase activity A compromised cardiac function is often seen in elderly cancer patients receiving doxorubicin therapy.
25665036
USP7 affects KMT2E
| 5
USP7 activates KMT2E.
| 3
USP7 activates KMT2E. 2 / 2
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Loss of USP7 induced degradation of MLL5 protein.
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Conversely, overexpression of USP7, but not a catalytically inactive USP7 mutant, led to decreased ubiquitylation and increased MLL5 stability.
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Mutated USP7 activates KMT2E. 1 / 1
| 1
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Conversely, overexpression of USP7, but not a catalytically inactive USP7 mutant, led to decreased ubiquitylation and increased MLL5 stability.
26678539
USP7 inhibits KMT2E.
| 2
USP7 inhibits KMT2E. 2 / 2
| 2
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Thus, OGT, USP7 and MLL5 form a highly organized protein complex through specific interactions among domains, and the absence of either USP7 or OGT leads to enhanced ubiquitylation and accelerated degradation of MLL5 protein.
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Absence of either OGT or USP7 triggers rapid degradation of MLL5 proteins via the ubiquitin-proteasomal pathway.
26678539
USP7 affects CASP1
| 5
USP7 decreases the amount of CASP1.
| 2
USP7 decreases the amount of CASP1. 2 / 2
| 2
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The expressions of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was attenuated by USP7 KD or USP7 inhibitor (XREF_FIG), were significantly enhance by the H 2 O 2 treatment as shown in western blotting results.
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ELISA and Western blotting results indicated that USP7 overexpression significantly increased IL-1beta and IL-18 levels as well as the expression of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was decreased by USP7 KD or apocynin (XREF_FIG).
33584299
USP7 activates CASP1.
| 2
USP7 activates CASP1. 2 / 2
| 2
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Results also indicated that MIA significantly upregulated USP7, NOX4, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was attenuated by the inhibition of USP7 with P22077 (XREF_FIG).
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The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1beta and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition.
33584299
USP7 increases the amount of CASP1.
| 1
USP7 increases the amount of CASP1. 1 / 1
| 1
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ELISA and Western blotting results indicated that USP7 overexpression significantly increased IL-1beta and IL-18 levels as well as the expression of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was decreased by USP7 KD or apocynin (XREF_FIG).
33584299
USP7 affects BUB3
| 3
USP7 decreases the amount of BUB3.
| 1
USP7 decreases the amount of BUB3. 1 / 3
| 1
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USP7 depletion caused a decrease in Bub3 protein levels and stability of Bub3 (cycloheximide treated cells, CHX), for both endogenous and over-expressed protein.
25003721
USP7 inhibits BUB3.
| 1
USP7 inhibits BUB3. 1 / 1
| 1
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Next, we tested whether the loss of USP7 would cause Bub3 destabilization.
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USP7 activates BUB3.
| 1
USP7 activates BUB3. 1 / 1
| 1
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Among those identified were DNMT1, RAE1, Bub3 and Nup98, the stability and functions of which are potentially regulated by Hausp.
19946331
TSPYL5 affects USP7
| 5
TSPYL5 decreases the amount of USP7.
| 3
TSPYL5 decreases the amount of USP7. 2 / 2
| 2
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Recently, TSPYL5 as an inhibitory protein for HAUSP was identified repressing the expression of HAUSP gene XREF_BIBR.
26238070
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To explore the mechanism underlying downregulation of the USP7 level by TSPY1 and TSPYL5, we treated cells overexpressing TSPY1 and TSPYL5 with a protein biosynthesis inhibitor, cycloheximide (CHX), and observed more obvious degradation of USP7; this effect could be inhibited by MG132 treatment.
29748603
Modified TSPYL5 decreases the amount of USP7. 1 / 1
| 1
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TSPYL5 is frequently overexpressed in breast cancer, and the study showed that an increasing level of TSPYL5 decreased USP7/HAUSP expression and led to the accumulation of p53 ubiquitination [29].
| PMC
TSPYL5 inhibits USP7.
| 2
TSPYL5 inhibits USP7. 2 / 2
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These observations suggest that TSPY1 and TSPYL5 can induce USP7 degradation via the 26S proteasome system.
29748603
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USP7 is the deubiquitylase for the p53 tumour suppressor and TSPYL5 reduces the activity of USP7 towards p53, resulting in increased p53 ubiquitylation.
21170034
PPM1G affects USP7
| 3
PPM1G inhibits USP7. 3 / 4
| 3
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Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.
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CK2 's stabilization of USP7 further contributes to MDM2 stabilization and downregulation of p53, and after ionizing radiation, the ATM dependent protein phosphatase PPM1G downregulates USP7, reversing its effects on MDM2 and p53 [XREF_BIBR].
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The authors demonstrated that USP7 degradation is initiated by the PPM1G protein phosphatase, which is activated by ATM dependent phosphorylation in response to DNA damage.
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N-ethylmaleimide affects USP7
| 3
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As expected, NEM inhibited USP2, USP7, and SENP2 with EC 50 values of 1.9 6 0.2 mM, 1.4 6 0.07 mM, and 1.3 6 0.2 mM, respectively ( Fig. 5A-C) .
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On the other hand, NEM was also inhibiting USP7 in both cells ( xref ) and brain ( xref ), however, in a non-selective way as shown by the overall decrease in HA signal at high concentrations of the compound.
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As expected, NEM inhibited USP2, USP7, and SENP2 with EC50 values of 1.9 ± 0.2 mM, 1.4 ± 0.07 mM, and 1.3 ± 0.2 mM, respectively (Fig. 5A–C).
18424514
CLSPN affects USP7
| 4
CLSPN activates USP7. 4 / 4
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By protecting Claspin from degradation, USP7 may directly impact the initiation as well as termination of Chk1 mediated signaling responses, and hence it will be important to address if and how the Claspin directed activity of USP7 is itself regulated during checkpoint responses.
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USP7 targets Claspin, another damage response mediator protein, to prevent its degradation.
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Only a slight increase in Chk1 levels was evident under these conditions, which further supports the notion that Claspin rather than Chk1 is a target of USP7.
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To clarify whether Claspin is a direct target of USP7, we tested whether the two proteins copurify in immunoprecipitation (IP) experiments.
19124652
C/VIF2 affects USP7
| 4
C/VIF2 inhibits USP7. 4 / 4
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Comparative kinetic analysis showed that while the vif1 peptide weakly attenuated HAUSP DUB activity, the vif2 peptide completely suppressed HAUSP DUB activity (XREF_FIG, right panel).
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These results thus further corroborate the notion that vif1 interferes with HAUSP substrate binding, while vif2 inhibits HAUSP DUB activity.
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HAUSP regulates the activities of MDM2 and p53 by deubiquitination, while vif1 and vif2 antagonize HAUSP and promote p53 dependent apoptosis XREF_BIBR.
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2.5.2 Vif1 and vif2 : Peptide inhibitors of HAUSP deubiquitinase (US20140073585A1).
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ATF3 affects USP7
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ATF3 activates USP7. 3 / 4
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However, it was unlikely that ATF3 directly regulates the USP7 deubiquitinase activity as pre-incubation of ATF3 with the ubiquitinated Tip60 protein, but not with USP7, appeared to be required for the ATF3 deubiquitination promoting effect as revealed by the in vitro ubiuiqitination assays (XREF_SUPPLEMENTARY).
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Whereas USP7 indeed increased the Tip60 expression level and concurrently decreased the amount of ubiquitinated Tip60, ATF3 expression promoted the effects of USP7 on Tip60 expression (XREF_FIG, lanes 3 vs. lane 2, and lane 5 vs. lane 4) and ubiquitination (XREF_SUPPLEMENTARY, lane 3 vs. lane 2), suggesting that ATF3 might promote USP7 mediated deubiqutination of Tip60.
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As expected, recombinant USP7 catalyzed removal of ubiquitin moieties from Tip60 (XREF_FIG, lane 2 vs. lane 1), and this effect was largely enhanced by ATF3 (XREF_FIG, lane 3).
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USP7 affects washc1
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USP7 activates washc1.
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USP7 activates washc1. 3 / 3
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To investigate how USP7 supports MAGE-L2-TRIM27 and WASH mediated protein recycling, we investigated whether USP7 controls the steady state levels or localization of any of the known components of the endosomal protein recycling pathway, including the important WASH actin assembly and retromer coat like complexes.
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USP7 Acts as a Molecular Rheostat to Promote WASH Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder.
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Taken together, these findings suggest that the USP7 deubiquitinating enzyme forms a stable complex with the MAGE-L2-TRIM27 E3 ubiquitin ligase and that all three proteins work in concert to control W[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7 inhibits washc1.
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USP7 inhibits washc1. 1 / 1
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This lead us to hypothesize that in addition to preventing TRIM27 auto-ubiquitination and degradation, USP7 also prevents over-activation of WASH and improper CI-M6PR recycling by precisely tuning WASH ubiquitination and endosomal actin levels.
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USP7 affects signal transduction
| 1 3
USP7 activates signal transduction. 3 / 3
| 1 2
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Independently of its action on p53 , USP7 modulates various pathways in homeostasis or during oncogenesis by targeting a large panel of substrates involved in cell cycle , DNA damage response , immune response , signal transduction , neuronal differentiation , and epigenetic regulation [ 7 , 9 ] .
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Moreover, USP7 siRNA blocked the activation of Akt/ERK signaling pathway.
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Overall, USP7 overexpression could promote OS cell metastasis by activating the Wnt and beta-catenin signalling pathway by inducing EMT, suggesting that USP7 is a potential therapeutic target for OS.
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USP7 bound to CTNNB1 activates signal transduction. 1 / 1
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Notably, USP7 can directly bind with beta-catenin to activate the Wnt and beta-catenin signalling pathway and induce epithelial-mesenchymal transition (EMT) of OS cells.
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USP7 affects immune response
| 1 3
USP7 inhibits immune response.
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USP7 targeting modulates anti-tumor immune response by reprogramming Tumor associated Macrophages in Lung Cancer.
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Pharmacological inhibition of USP7 promotes antitumor immunity and contributes to colon cancer therapy.
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USP2b, USP3, USP18, USP25, UL36USP and HAUSP play a role of antivirus; while USP4, USP13, USP15 and USP17 negatively regulate antiviral immune response.
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USP7 activates immune response.
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USP7 activates immune response. 1 / 1
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Independently of its action on p53 , USP7 modulates various pathways in homeostasis or during oncogenesis by targeting a large panel of substrates involved in cell cycle , DNA damage response , immune response , signal transduction , neuronal differentiation , and epigenetic regulation [ 7 , 9 ] .
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USP7 inhibits homeostatic process.
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USP7 inhibits homeostatic process. 2 / 2
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Novel oncogenic mutations in the TP53, BRCA2, PTEN, IL7R, RAS, NOTCH1, ETV6, BCL11B, WT1, DNMT3A, PRC2, PHF6, USP7, KDM6A and an array of other genes disrupt the genetic and epigenetic homeostasis in T-ALL.
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XREF_BIBR, XREF_BIBR Indeed, recent findings suggest that haploinsufficiency or duplications of HAUSP disrupt neuronal homeostasis, giving rise to neurological and behavioral abnormalities, such as seizures, aggressiveness, hypotonia, intellectual disability, hypogonadism with clinical features of autism spectrum disorder and a condition similar to Schaaf-Yang syndrome.
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USP7 activates homeostatic process.
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USP7 activates homeostatic process. 2 / 2
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Independently of its action on p53, USP7 modulates various pathways in homeostasis or during oncogenesis by targeting a large panel of substrates involved in cell cycle, DNA damage response, immune response, signal transduction, neuronal differentiation, and epigenetic regulation [7, 9].
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Additionally, genomic duplications involving USP7 were reported in individuals with autism spectrum disorder (Sanders et al., 2011), further supporting the idea of dosage sensitivity, with both too li[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
26365382
USP7 affects cell
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USP7 inhibits cell.
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USP7 inhibits cell. 2 / 2
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Both physical interaction with DNMT1 and deubiquitinase activity are required for USP7 to inhibit DNMT1 replication fork association and DNA methylation in USP7-KO cells .
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Silencing of FOXO6 physically reduced USP7 , resulting in promoted EC apoptosis A previous study13 showed that USP7 transcriptional activation by FOXO6 suppresses lung cancer progression and that USP7 inhibited cell proliferation in EC .
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USP7 activates cell.
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USP7 activates cell. 2 / 2
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We also observed that loss of USP7 led to reduced cell proliferation and increased population of G2 phase cells ( Supplementary Fig. S2f ) , consistent with an increased p21 expression .
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USP7 inhibitors effectively impair proliferation in AML cells in vitro , also independent of the USP7-MDM2-TP53 axis , and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts .
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USP7 affects PODXL
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USP7 activates PODXL. 3 / 3
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Our finding that USP7 is an enhancer of Pc and is associated with polytene chromosomes suggested a function in chromatin regulation.
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Both GMPS and USP7 contribute to Pc directed silencing of homeotic genes, establishing that they function in the same biological pathway in vivo.
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Therefore, we tested whether USP7 contributed to Pc mediated silencing of the homeotic genes.
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USP7 bound to GMPS activates PODXL. 1 / 1
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Our finding that the USP7 and GMPS complex is an enhancer of Pc mediated silencing that deubiquitylates H2B lends further supports to this notion.
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USP7 affects PCGF2
1 | 3
USP7 activates PCGF2.
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USP7 activates PCGF2. 3 / 3
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Importantly, knockdown of either USP7 or USP11 reduces the total and chromatin bound pool of BMI1 and MEL18, and the effects can be mitigated by inhibiting proteasome function.
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Knockdown of USP7 or USP11 causes increased turnover of chromatin bound MEL18 and BMI1, whereas over-expression of the USPs reduces the levels of mono- and poly-ubiquitination of these proteins [XREF_BIBR].
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Knockdown of USP7 or USP11 causes increased turnover of chromatin bound MEL18 and BMI1, whereas over-expression of the USPs reduces the levels of mono- and poly-ubiquitination of these proteins.
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USP7 increases the amount of PCGF2.
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Catalytically active USP7 increases the amount of PCGF2. 1 / 1
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Regulation of the stability of the PRC1 complex also appears to be another facet, as the de-ubiquitination of the PRC1 components BMI1 and MEL18 by the ubiquitin-specific proteases 7 and 11 has been shown to increase their abundance (Maertens et al., 2010), whereas the loss of these ubiquitin-specific proteases promotes INK4A transcriptional activation.
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USP7 affects Osteoarthritis
| 1 3
USP7 activates Osteoarthritis.
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USP7 activates Osteoarthritis. 3 / 3
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Both of the in vitro and in vivo data in this study indicated for the first time that USP7 promoted the progression of OA via NOX4/ROS/NLPR3 signaling.
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Both of the in vitro and in vivo data in this study indicated for the first time that USP7 promoted the progression of OA via NOX4 / ROS / NLPR3 signaling .
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These data suggested that NOX4 dependent ROS production played a crucial role in the progression of USP7 mediated OA.
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USP7 inhibits Osteoarthritis.
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USP7 inhibits Osteoarthritis. 1 / 1
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NOX4 inhibitor was applied to study the involvement of NOX4 in USP7 mediated OA development.
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USP7 affects GLI1
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USP7 increases the amount of GLI1.
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USP7 increases the amount of GLI1. 2 / 2
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Knockdown of endogenous hausp suppressed the expression of Shh reporter gene and attenuated endogenous Gli levels.
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Knockdown of endogenous hausp suppressed the expression of Shh reporter gene and attenuated endogenous Gli levels (XREF_FIG).
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USP7 decreases the amount of GLI1.
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USP7 decreases the amount of GLI1. 2 / 2
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Knockdown of endogenous hausp suppressed the expression of Shh reporter gene and attenuated endogenous Gli levels.
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Knockdown of endogenous hausp suppressed the expression of Shh reporter gene and attenuated endogenous Gli levels (XREF_FIG).
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USP7 affects Arp2_3_protein
| 4
USP7 decreases the amount of Arp2_3_protein.
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USP7 decreases the amount of Arp2_3_protein. 2 / 2
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Analysis of these cells revealed that knockdown of USP7 in TRIM27 3KR cells significantly increased Arp2/3 and F-actin levels on FAM21 positive endosomes.
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Analysis of these cells revealed that knockdown of USP7 in TRIM27 3KR cells significantly increased Arp2/3 and F-actin levels on FAM21 positive endosomes (XREF_FIG).
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USP7 activates Arp2_3_protein.
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USP7 activates Arp2_3_protein. 2 / 2
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Furthermore, knockout of one USP7 allele in HCT116 cells (USP7 +/-) resulted in impaired CI-M6PR recycling, decreased Arp2/3 localization to VPS35 positive endosomes, and decreased F-actin accumulatio[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Furthermore, knockout of one USP7 allele in HCT116 cells (USP7 +/-) resulted in impaired CI-M6PR recycling (XREF_FIG), decreased Arp2/3 localization to VPS35 positive endosomes (XREF_FIG and XREF_SUPPLEMENTARY), and decreased F-actin accumulation on VPS35 positive endosomes (XREF_FIG and XREF_SUPPLEMENTARY).
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PTEN affects USP7
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PTEN deubiquitinates USP7.
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PTEN deubiquitinates USP7. 3 / 3
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Furthermore, NPM1c+ binds and inhibits the PTEN deubiquitinating enzyme HAUSP, resulting in PTEN cytoplasmic polyubiquitinilation and degradation [XREF_BIBR].
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For instance, cytosolic NPM1 binds and inhibits caspases 6 and 8 38 and the PTEN deubiquitinating enzyme HAUSP, resulting in PTEN cytoplasmic polyubiquitinilation and degradation.
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Furthermore NPM1c + interacts with and inhibits the PTEN deubiquitinating enzyme HAUSP, resulting in PTEN polyubiquitination and degradation [27].
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PTEN activates USP7.
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PTEN activates USP7. 1 / 1
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Recent results showed that HAUSP deubiquitinates PTEN to cause its nuclear exclusion and leads to tumour progression, supporting the oncogenic role of HAUSP XREF_BIBR.
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DNMT1 affects USP7
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DNMT1 inhibits USP7.
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DNMT1 inhibits USP7. 1 / 2
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Thus , our data revealed that loss of USP7 variably reduced DNMT1 and UHRF1 protein stability , presumably due to its deubiquitinase activity toward DNMT1 and UHRF1 as reported previously38-41 .
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DNMT1 activates USP7.
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DNMT1 activates USP7. 1 / 2
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The other one uses (DNMT1) Lys1115→ (USP7) Asp682 as the mediator, such as (DNMT1) Tyr524→Gly1534→Gln1536→Ser1524→Phe1522→Thr1366→Thr1364→Val1333→Pro990→Arg992→Gly994→Ile996→Val935→Gln1123→Lys1121→Lys1119→Lys1117→Lys1115→ (USP7) Asp682→Asp680→Lys678→Leu676→Ala674.
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USP7 affects IL1B
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USP7 activates IL1B.
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USP7 activates IL1B. 2 / 2
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ELISA results indicated that H2O2 treatment significantly increased IL-1beta and IL-18 , which was decreased by USP7 KD or USP7 inhibitor ( Figure 2C ) .
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Moreover, XREF_FIG shows MIA enhanced IL-1beta and IL-18 which was suppressed by USP7 inhibition.
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USP7 inhibits IL1B.
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USP7 inhibits IL1B. 1 / 1
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ELISA results indicated that H 2 O 2 treatment significantly increased IL-1beta and IL-18, which was decreased by USP7 KD or USP7 inhibitor (XREF_FIG).
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USP7 increases the amount of IL1B.
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USP7 increases the amount of IL1B. 1 / 1
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ELISA and Western blotting results indicated that USP7 overexpression significantly increased IL-1beta and IL-18 levels as well as the expression of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was decreased by USP7 KD or apocynin (XREF_FIG).
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USP7 affects IL18
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USP7 increases the amount of IL18.
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USP7 increases the amount of IL18. 2 / 2
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The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1beta and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition.
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ELISA and Western blotting results indicated that USP7 overexpression significantly increased IL-1beta and IL-18 levels as well as the expression of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was decreased by USP7 KD or apocynin (XREF_FIG).
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USP7 inhibits IL18.
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USP7 inhibits IL18. 1 / 1
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ELISA results indicated that H 2 O 2 treatment significantly increased IL-1beta and IL-18, which was decreased by USP7 KD or USP7 inhibitor (XREF_FIG).
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USP7 activates IL18.
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USP7 activates IL18. 1 / 1
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Moreover, XREF_FIG shows MIA enhanced IL-1beta and IL-18 which was suppressed by USP7 inhibition.
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USP7 affects CDKN1A
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USP7 activates CDKN1A.
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USP7 activates CDKN1A. 2 / 2
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Next we tested whether USP7 enhanced p53 function by examining the induction of p21 in H1299 cells after transfection of a p53 expressing plasmid alone or in combination with a plasmid expressing either WT USP7 or a USP7 mutant (XREF_FIG).
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Consistent with the ChIP results, coexpression of WT USP7 or C223S led to induction of p21 (lanes 3 and 4).
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USP7 increases the amount of CDKN1A.
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Modified USP7 increases the amount of CDKN1A. 1 / 1
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Consistent with our in vitro observations, we found that overexpression of catalytically inactive USP7 in cells promotes p53 binding to its target sequences and p21 expression, without increasing the levels of p53 protein.
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USP7 decreases the amount of CDKN1A.
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USP7 decreases the amount of CDKN1A. 1 / 1
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HCT116 USP7 -/- cells grow extremely slowly because USP7 knockout leads to constitutively high level of p53 and p21.
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USP7 affects IRS2
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USP7 increases the amount of IRS2.
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Modified USP7 increases the amount of IRS2. 1 / 1
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By contrast, over-expression of dominant negative USP7 (USP7 CS, where the single cysteine residue in the catalytic center was substituted with serine [19]) decreased IRS-2 protein levels, an effect p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7 increases the amount of IRS2. 1 / 1
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Moreover, in H4IIE cells, knockdown of USP7 decreased IRS-2 protein levels.
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USP7 decreases the amount of IRS2.
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Modified USP7 decreases the amount of IRS2. 1 / 1
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By contrast, over-expression of dominant negative USP7 (USP7 CS, where the single cysteine residue in the catalytic center was substituted with serine [19]) decreased IRS-2 protein levels, an effect p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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USP7 activates IRS2.
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USP7 activates IRS2. 1 / 1
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All of these results support our hypothesis that USP7 prevents IRS-2 degradation by deubiquitinating activity.
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USP7 affects ATF3
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USP7 inhibits ATF3.
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USP7 inhibits ATF3. 1 / 1
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Indeed, a USP7 specific inhibitor or USP7 siRNA could abolish the effects of ATF3 on Tip60 (XREF_FIG), arguing for the notion that ATF3 mediated Tip60 stabilization is dependent on USP7.
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USP7 increases the amount of ATF3.
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USP7 increases the amount of ATF3. 1 / 1
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Interestingly, both the USP7 inhibitor and the USP7 siRNA appeared to increase ATF3 expression (XREF_FIG, lane 3).
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USP7 decreases the amount of ATF3.
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USP7 decreases the amount of ATF3. 1 / 1
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While USP7 inhibition could result in downregulation of MDM2 19 thereby preventing ATF3 from MDM2 mediated ubiquitination and degradation 28, it might also be that the increased ATF3 expression was caused by USP7 catalyzed deubiquitination of ATF3.
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USP7 activates ATF3.
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USP7 activates ATF3. 1 / 1
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Indeed, a USP7 specific inhibitor or USP7 siRNA could abolish the effects of ATF3 on Tip60 (XREF_FIG), arguing for the notion that ATF3 mediated Tip60 stabilization is dependent on USP7.
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Pmt3 affects USP7
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Pmt3 activates USP7. 3 / 3
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Remarkably, however, and in contrast to c-Rel and p65, the deletion of Ubl2 did not inhibit the interaction of USP7 with RelB (XREF_FIG E).
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The results of these experiments demonstrated that the deletion of Ubl2 did not inhibit the interaction of USP7 with p53 or EBNA1 (XREF_FIG, A and B).
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However, deletion of Ubl2, either alone or in combination with the deletion of Ubl3, Ubl4, and Ubl5, prevented the interaction of USP7 with p65 (XREF_FIG, C and F).
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Pimozide affects USP7
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Pimozide inhibits USP7. 3 / 3
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Pimozide weakly inhibits USP7 , and is selective against a wide set of cysteine proteases .
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Pimozide inhibits USP7 with an IC 50 of 47 muM, 24-fold higher than that measured for USP1 and UAF1.
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Pimozide weakly inhibits USP7, and is selective against a wide set of cysteine proteases.
| PMC
USP7 affects TRIP12
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USP7 activates TRIP12. 2 / 3
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Thus, USP7 increases the stability of TRIP12, whereas the TRIP12 does the opposite for USP7.
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Similarly TRIP12 was consistently decreased by USP7 silencing, although in most cases there was little to no rescue of the levels with MG132 treatment.
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USP7 affects Multiple Myeloma
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USP7 inhibits Multiple Myeloma. 2 / 3
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A recent study demonstrated that inhibition of ubiquitin specific protease-7 (USP7), which normally stabilizes MDM2, triggers apoptosis in bortezomib resistant MM cells, confirming the idea of p53 downregulation as a DR mechanism in MM [XREF_BIBR].
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A class of dual small molecule inhibitors of USP7 and USP47 has been identified to promote p53 activity and apoptosis in MM and B-cell leukemia cells in vitro and xenograft models.
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USP7 affects DNA repair
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USP7 activates DNA repair. 3 / 3
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Additionally, in a series of in vitro bladder cancer cells we have investigated whether the pharmacological inhibition of USP7, by lowering the levels of CCDC6, was able to impair the DNA repair processes by homologous recombination (HR), favouring the bladder cancer cells sensitivity to PARP-inhibitors.
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Pharmacological inhibition of USP7 controls CCDC6 stability and impairs the DSBs DNA repair in prostate cancer cells.
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Accordingly, an siRNA knockdown of USP7 should lead to a reduced amount of BER enzymes and impair DNA repair.
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USP7 affects DAXX
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USP7 activates DAXX. 1 / 3
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Binding of Hausp has been shown to increase the stability of Daxx by reducing its ubiquitinylation.
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Phosphatase affects USP7
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Phosphatase inhibits USP7. 3 / 3
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Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.
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CK2 's stabilization of USP7 further contributes to MDM2 stabilization and downregulation of p53, and after ionizing radiation, the ATM dependent protein phosphatase PPM1G downregulates USP7, reversing its effects on MDM2 and p53 [XREF_BIBR].
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The authors demonstrated that USP7 degradation is initiated by the PPM1G protein phosphatase, which is activated by ATM dependent phosphorylation in response to DNA damage.
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PPIA affects USP7
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PPIA inhibits USP7. 3 / 3
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CYPA overexpression could antagonize the host barrier, USP7.
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Moreover, CYPA overexpression markedly antagonized the connection of EBNA1 to Ubiquitinspecific protease 7 (USP7), which is a strong host barrier with a role of inhibiting EBV genome replication.
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Elevated CYPA levels remarkably antagonize USP7 in the interaction with EBNA1.
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PML affects USP7
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PML inhibits USP7. 3 / 3
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47 In addition, PML negatively regulates the function of HAUSP through DAXX to further modulate PTEN activity in a context specific manner.
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PML is required to inhibit USP7, thus preventing the deubiquitination of the tumor suppressing phosphatase PTEN.
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Conversely, PML negatively regulates the DUB HAUSP and USP7, thus opposing PTEN deubiquitination and cytoplasmic translocation.
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NOTCH1 affects USP7
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NOTCH1 increases the amount of USP7. 3 / 3
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Previous reports have documented the transcriptional regulation of USP7, for instance in T-cell acute lymphoblastic leukemia (T-ALL) in which the transcription factor NOTCH1 induces USP7 gene expression, and where USP7 controls the stability of NOTCH1 and the JMJD3 histone demethylase through a positive regulatory loop [XREF_BIBR, XREF_BIBR].
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Previous reports have documented the transcriptional regulation of USP7, for instance in T-cell acute lymphoblastic leukemia (T-ALL) in which the transcription factor NOTCH1 induces USP7 gene expression, and where USP7 controls the stability of NOTCH1 and the JMJD3 histone demethylase through a positive regulatory loop [37, 38].
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The USP7 gene locus is bound by NOTCH1, which significantly upregulates USP7 levels and activity for USP7 in a subset of T-cell Acute Lymphoblastic Leukemia (T-ALL) cases [XREF_BIBR].
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Hedgehog affects USP7
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Hedgehog activates USP7. 3 / 3
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Zhou, et al. showed that Hh stimulates the binding of a ubiquitin-specific protease USP7 to Ci, which positively regulates Hh signaling activity through inhibiting Ci ubiquitination and degradation mediated by both Cul1-Slimb and Cul3-HIB E3 ligases [51].
| PMC
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Here, we show that Hh stimulated Usp7 binding to Ci may provide another mechanism to attenuate Hib mediated degradation of Ci A.
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Here, we show that Hh stimulated Ci-Cos2 dissociation may also facilitate the binding of Usp7 to Ci, leading to deubiquitination of Ci.
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VIRF-4 affects USP7
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VIRF-4 inhibits USP7.
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VIRF-4 inhibits USP7. 2 / 2
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An in vitro DUB assay of immunopurified Flag-HAUSP complexes with K48 linked 3-7 polyubiquitin chains showed that vIRF4 effectively suppressed HAUSP DUB activity in a binding dependent manner.
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In summary, our study shows that vIRF4 derived short vif1 and vif2 peptides comprehensively suppress HAUSP activity, effectively restoring p53 dependent apoptosis in wild-type p53 carrying cancer cells and suppressing tumor growth in a mouse xenograft model.
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VIRF-4 activates USP7.
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VIRF-4 activates USP7. 1 / 1
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VIRF4 independently targets HAUSP and MDM2 to downregulate p53.
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Cisplatin affects USP7
1 | 2
Cisplatin activates USP7.
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Cisplatin activates USP7. 2 / 2
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Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7 and hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity.
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There is a study that suggested that cisplatin and paclitaxel promote miR-522 secretion from cancer-associated fibroblasts by activating the USP7/hnRNPA1 axis, leading to arachidonate lipoxygenase 15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately resulting in decreased chemo-sensitivity [37].
| PMC
Cisplatin decreases the amount of USP7.
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Cisplatin decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
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USP7 activates deoxyribonucleic acid.
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USP7 activates deoxyribonucleic acid. 2 / 2
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Our results indicate that inhibition of USP7 leads to a disruption of cell cycle progression , and triggers DNA damage and apoptosis .
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Regardless of this activity , USP7 inhibitors also generate DNA damage in a p53-independent manner .
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USP7 inhibits deoxyribonucleic acid.
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USP7 inhibits deoxyribonucleic acid. 1 / 1
| 1
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Ubiquitin-specific protease 7 ( USP7 ) triggers DNA damage in a concentration - and time-dependent manner .
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USP7 affects TBK1
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USP7 inhibits TBK1. 2 / 2
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In SeV infection there seems to be another mechanism at work ; the ubiquitin-specific peptidase 7 ( USP7 ) interacts with and stabilizes TRIM27 , promoting the degradation of TBK1 and suppressing the activation of IFN-beta ( Cai et al ., 2018 ) .
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In addition , USP13 removes K27-linked polyubiquitinchains from STING then decreases the antiviral immune response against DNA viruses by disrupting the recruitment of TBK1 , whereas USP7 removes K48-linked polyubiquitination from TRIM27 and promotes the degradation of TBK1 .
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USP7 bound to TRIM27 inhibits TBK1. 1 / 1
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In SeV infection there seems to be another mechanism at work; the ubiquitin-specific peptidase 7 (USP7) interacts with and stabilizes TRIM27, promoting the degradation of TBK1 and suppressing the activation of IFN-β (Cai et al., 2018) .
34925304
USP7 affects RNF168
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USP7 activates RNF168.
| 1
USP7 activates RNF168. 1 / 2
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USP7 deubiquitinase promotes ubiquitin dependent DNA damage signaling by stabilizing RNF168.
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USP7 decreases the amount of RNF168.
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USP7 decreases the amount of RNF168. 1 / 1
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We showed that USP7 disruption impairs H2A and ultraviolet radiation (UVR)-induced gammaH2AX monoubiquitination, and decreases the levels of pBmi1, Bmi1, RNF168 and BRCA1.
25894431
USP7 affects RELA
| 3
USP7 activates RELA.
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USP7 activates RELA. 2 / 2
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A study reported that USP7 is critical for target gene transcription, whereby USP7 targeted NF-kappaB p65 for K48 linked deubiquitination, increased the protein stability of p65, and ultimately led to increased transcription.
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Altogether, our findings highlighted that USP7 promoted the occurrence of LN by regulating the NF-kappaB p65 signaling pathway via stabilization of JMJD3.
33895173
USP7 inhibits RELA.
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USP7 inhibits RELA. 1 / 1
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We also found that overexpression of USP7 strongly suppressed translocation of p65 from the cytoplasm into the nucleus (XREF_FIG).
24832601
USP7 affects FOXO4
| 3
USP7 inhibits FOXO4.
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USP7 inhibits FOXO4. 2 / 2
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Consequently, USP7 expression inhibited FOXO4 transcriptional activity due to de-ubiquitination of FOXO4 and re-localization to the cytosol.
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For example, the deubiquitylase MATH-33 recently has been reported to stabilize and activate DAF-16 by antagonizing polyubiquitylation, while its mammalian counterpart USP7 and HAUSP inhibits FOXO1 and FOXO4 by decreasing their nuclear localization and transcriptional activity, respectively, by removing monoubiquitin moieties [XREF_BIBR - XREF_BIBR].
28562327
USP7 activates FOXO4.
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USP7 activates FOXO4. 1 / 1
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FOXO4 accumulation in the nucleus may be caused by weak deubiquitination of USP7 downregulation.
33869052
USP7 affects E1B-55K protein
| 3
USP7 increases the amount of E1B-55K protein.
| 2
USP7 increases the amount of E1B-55K protein. 2 / 2
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Both USP7 knockdown and inhibitor application severely reduced E1B-55K protein levels, and in the knockdown setting as well as after USP7 inhibitor application the half-life of E1B-55K was significantly shorter (XREF_SUPPLEMENTARY).
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Taken together, USP7 knockdown and knockout or inhibition led to greatly reduced E1B-55K protein levels, indicating a stabilizing role of USP7 for E1B-55K.
23555268
USP7 decreases the amount of E1B-55K protein.
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USP7 decreases the amount of E1B-55K protein. 1 / 1
| 1
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RNA interference mediated downregulation of USP7 severely reduced E1B-55K protein levels, but more importantly negatively affected adenoviral replication.
23555268
USP7 affects CRY2
| 2
USP7 activates CRY2.
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USP7 activates CRY2. 1 / 2
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This observation indicated that Usp7 knockdown decreased the steady state levels of CRY1 and CRY2 proteins.
27123980
USP7 increases the amount of CRY2.
| 1
Modified USP7 increases the amount of CRY2. 1 / 1
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The protein levels of Myc-CRY1 and Myc-CRY2 were increased by co-expression of Myc-USP7 in HEK293T/17 cells (XREF_FIG).
27123980
USP7 affects CDKN2A
| 2
USP7 decreases the amount of CDKN2A.
| 1
USP7 decreases the amount of CDKN2A. 1 / 2
| 1
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The role of HAUSP in the epigenetic modification of proteins and regulation of gene expression is evident from its ability to deubiquitinate polycomb group RING finger 2 (MEL18) and BMI1 (components of the multiprotein polycomb repressive complex, PRC1), subsequently repressing the expression of the tumor suppressor p16INK4a, various homeotic genes and hormone dependent genes.
29967688
USP7 increases the amount of CDKN2A.
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USP7 increases the amount of CDKN2A. 1 / 1
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For example, HAUSP modulates the level of the p16 INK4a and p53 tumor suppressors through changes in the stabilization of Bmi1 and Mel18 and Mdm2, respectively.
23483195
SLC4A1 affects USP7
| 1 2
SLC4A1 inhibits USP7.
| 1 1
SLC4A1 inhibits USP7. 2 / 2
| 1 1
eidos
In this study , we could show that DIs , especially those inhibiting USP7 and USP47 , enhance the entry of Gag into the UPS and thus into the MHC-I pathway , indicating that specific DUBs play an important role in the regulation of Gag ubiquitination .
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Cells were treated with the following DIs: P22077, which specifically inhibits the DUBs USP7 and USP47 [59], the DI P5091, which only inhibits USP7 [60], and the DI PR-619, that, in addition to USP7 and USP47, inhibits the DUBs Josephin domain containing 2 (JOSD2), deneddylase 1 (DEN1), UCH-L3, UCH-L5, USP2, 4, 5, 8, 15, 20, and 28 [59].
28805676
SLC4A1 activates USP7.
| 1
SLC4A1 activates USP7. 1 / 1
| 1
reach
Cells were treated with the following DIs: P22077, which specifically inhibits the DUBs USP7 and USP47 [59], the DI P5091, which only inhibits USP7 [60], and the DI PR-619, that, in addition to USP7 and USP47, inhibits the DUBs Josephin domain containing 2 (JOSD2), deneddylase 1 (DEN1), UCH-L3, UCH-L5, USP2, 4, 5, 8, 15, 20, and 28 [59].
28805676
NMRAL1 affects USP7
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NMRAL1 activates USP7.
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NMRAL1 activates USP7. 2 / 2
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The results showed that knockout of HSCARG attenuated the blocking effect of USP7 and promoted the degradation of IkBalpha (XREF_FIG).
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And USP7 partially rescued the growth rate of HSCARG -/- cells, while HSCARG did not rescue the growth rate of USP7 -/- cells.
24711370
NMRAL1 inhibits USP7.
| 1
NMRAL1 bound to IKBKG inhibits USP7. 1 / 1
| 1
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NFkappaB can be directly deubiquitinated by HAUSP 87 or can be indirectly regulated by deubiquitination of its upstream factors, such as TRAF6, 24 NEMO (IKK-gamma) XREF_BIBR, XREF_BIBR (HSCARG interacts with NEMO to suppress its polyubiquitination by recruiting HAUSP 91), NIMA (Never In Mitosis Gene A)-related kinase 2 (Nek2), a centrosomal serine/threonine kinase (HAUSP stabilizes Nek2 leading to activation of NFkappaB pathway in multiple myeloma).
29967688
MIA affects USP7
| 1 2
MIA activates USP7.
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MIA activates USP7. 2 / 2
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reach
Results also indicated that MIA significantly upregulated USP7, NOX4, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was attenuated by the inhibition of USP7 with P22077 (XREF_FIG).
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MIA was used to induce OA model rats to study the role of USP7 in the OA process.
33584299
MIA inhibits USP7.
| 1
MIA inhibits USP7. 1 / 1
| 1
eidos
Results also indicated that MIA significantly upregulated USP7 , NOX4 , NLRP3 , GSDMD-N , active caspase-1 , pro-caspase-1 , MMP1 , and MMP13 , which was attenuated by the inhibition of USP7 with P22077 ( Figures 6C , D ) .
33584299
IL6 affects USP7
| 3
IL6 decreases the amount of USP7.
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IL6 decreases the amount of USP7. 2 / 2
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Our data are in accordance with a recent study by XREF_BIBR that reports that, in colon tumors, IL-6 can inhibit USP7 expression in a STAT3 dependent manner.
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In addition to observing that LPS could disrupt the association between USP7 and Foxp3, Yang et al. (2012) also found that in colon tumours, IL-6 inhibits USP7 expression in a STAT3 dependent manner, and the USP7-Foxp3 association was prolonged by this reduction in USP7 expression.
29352742
IL6 inhibits USP7.
| 1
IL6 inhibits USP7. 1 / 1
| 1
reach
To analyze whether IL-6 could also disrupt association of Foxp3 and USP7, we treated freshly isolated Foxp3-GFP Treg cells with IL-6 for 1 hr, and a PLA was performed.
23973222
FTO affects USP7
| 3
FTO increases the amount of USP7.
| 2
FTO increases the amount of USP7. 2 / 2
| 2
reach
Li et al.88 found that FTO promotes the proliferation of NSCLC by increasing the expression of USP7.
| PMC
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FTO promotes proliferation and colony formation of lung cancer cells by increasing the expression of USP7 (ubiquitin specific protease 7).
33552994
FTO inhibits USP7.
| 1
Modified FTO inhibits USP7. 1 / 1
| 1
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On the other hand, high expression of FTO in lung cancer was found to decrease the m6A levels of ubiquitin specific peptidase 7 (USP7), improve the mRNA stability of USP7, and promote the occurrence of NSCLC [XREF_BIBR].
32398132
USP7 affects XPC
| 3
USP7 inhibits XPC.
| 1
USP7 inhibits XPC. 1 / 1
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Overexpression of wild-type USP7, but not its catalytically inactive or interaction defective mutants, reduces the ubiquitinated forms of XPC.
25118285
USP7 decreases the amount of XPC.
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USP7 decreases the amount of XPC. 1 / 1
| 1
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Inhibition of USP7 increases XPC ubiquitination level, and without USP7, cells have decreased efficiency in repairing UV lesions [XREF_BIBR, XREF_BIBR].
30831436
USP7 activates XPC.
| 1
USP7 activates XPC. 1 / 1
| 1
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USP7 targeting XPC and CSB.
27316462
USP7 affects USP11
| 3
USP7 inhibits USP11.
| 1
USP7 inhibits USP11. 1 / 1
| 1
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Interestingly, knockdown of USP7 caused a concomitant decrease in the levels of chromatin bound USP11, underscoring the close association between these two proteins (XREF_SUPPLEMENTARY).
20601937
USP7 increases the amount of USP11.
| 1
Modified USP7 increases the amount of USP11. 1 / 1
| 1
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Overexpression of WT USP7, but not the C223S catalytically inactive mutant of USP7, was found to increase the levels of DDX24, DHX40 and USP11.
30367141
USP7 activates USP11.
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USP7 activates USP11. 1 / 1
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Although we saw some evidence of USP7 mediated stabilization of USP11 in AGS cells, the results in CNE2Z and HCT116 cells suggest that USP7 does not consistently stabilize this protein.
30367141
USP7 affects CDKN1B
| 1 2
USP7 increases the amount of CDKN1B.
| 1
USP7 increases the amount of CDKN1B. 1 / 1
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Our results showed that FOXO4 was mainly present in the nuclear compartment after USP7 downregulation (XREF_FIG), which ultimately promoted p27 kip1 expression (XREF_FIG).
33869052
USP7 decreases the amount of CDKN1B.
| 1
USP7 decreases the amount of CDKN1B. 1 / 1
| 1
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USP7 knockdown decreases Akt phosphorylation and then causes FOXO phosphorylation reduction, which ultimately increases FOXO accumulation in the nucleus and promotes P27 kip1 gene expression that arrests the cell cycle (XREF_FIG).
33869052
USP7 activates CDKN1B.
| 1
USP7 activates CDKN1B. 1 / 1
| 1
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Our results showed that FOXO4 was mainly present in the nuclear compartment after USP7 downregulation ( Figures 4C , D ) , which ultimately promoted p27kip1 expression ( Figure 4E ) .
33869052
USP7 affects AMPK
| 3
USP7 inhibits AMPK.
| 1
USP7 inhibits AMPK. 1 / 1
| 1
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Taken together, our results suggest that loss of USP7 function inhibits the melanoma cell cycle and promotes cell apoptosis by mediating AMPK and PI3K/Akt/FOXO signaling pathway activity.
33869052
USP7 decreases the amount of AMPK.
| 1
USP7 decreases the amount of AMPK. 1 / 1
| 1
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The results showed that inhibition of USP7 increases expression of the AMPK beta (PRKAB1), caspase 7 (CASP7), and protein phosphatase 2 subunit B R3 isoform (PPP2R3A), while attenuating expression of C subunit of vacuolar ATPase (ATP6V0C), and peroxisomal biogenesis factor 11 beta (PEX11B).
33869052
USP7 activates AMPK.
| 1
USP7 activates AMPK. 1 / 1
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Accordingly, USP7 loss inhibits melanoma growth by partially activating the AMPK signaling pathway.
33869052
Tx affects USP7
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Tx inhibits USP7. 2 / 2
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Our laboratory has previously found that TX disrupted MDM2, DAXX, and HAUSP complex, reduced expression of MDM2, and activated p53 in APL cell lines [35].
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TX disrupts MDM2, DAXX, and HAUSP complex.
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Reactive oxygen species inhibits USP7. 2 / 2
| 2
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Importantly, this in vitro ROS-induced inhibition of USP7 is also fully reversible by DTT ( xref ).
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In agreement with their endogenous counterparts, ectopically expressed Flag-USP7 could be inhibited by ROS, while Flag-USP28 was more refractory to this inhibition ( xref ).
23219552
Parthenolide affects USP7
| 2
Parthenolide inhibits USP7. 2 / 2
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Here, we report that sesquiterpene lactone parthenolide (PTL) inhibits USP7 activity, assessed with deubiquitinating enzyme activity assays, including fluorogenic Ub-AMC and Ub-Rho 110, Ub-VME/PA labeling and Di-Ub hydrolysis assays.
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Parthenolide inhibits ubiquitin specific peptidase 7 (USP7), Wnt signaling, and colorectal cancer cell growth.
32029476
Hydrogen peroxide affects USP7
| 1 1
Hydrogen peroxide activates USP7. 2 / 2
| 1 1
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Cells transfected with lipofectamine (Lipo) only and cells transfected with lipofectamine and USP7 siRNA duplexes for 72h were treated with hydrogen peroxide and collected at different time points after treatment.
21138959
eidos
H2O2 increased USP7 expression and caused damage in rat chondrocytes .
33584299
Doxycycline affects USP7
| 2
Doxycycline decreases the amount of USP7. 2 / 2
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Addition of doxycycline to the culture medium reduced USP7 expression as measured at both mRNA (XREF_SUPPLEMENTARY) and protein (XREF_FIG) levels, and as expected, USP7 silencing stabilized p53, resulting in induction of its target genes (XREF_FIG; XREF_SUPPLEMENTARY).
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The addition of doxycycline to the culture medium reduced USP7 expression as measured at both the mRNA and protein levels, and as expected, USP7 silencing stabilized p53, resulting in induction of its[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Chlorpyrifos affects USP7
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Chlorpyrifos increases the amount of USP7. 2 / 2
2 |
ctd
No evidence text available
20350560
ctd
No evidence text available
21356183
Cas9 affects USP7
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Cas9 activates USP7. 2 / 2
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CRISPR/Cas9-mediated inactivation of USP7 in p53-deficient lung cancer H1299 line resulted in advanced cell proliferation in vitro and in xenograft tumor in vivo.
34580281
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USP7 knockout GT1-7 cells were generated by co-transfection of plasmids encoding GFP-Cas9 and a gRNA plasmid targeting USP7 (5 '- GGTTGCCTCGGAGCGCCAAC-3 ').
26365382
Barium(2+) affects USP7
| 1 1
Barium(2+) inhibits USP7. 2 / 2
| 1 1
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Our preliminary data suggests that BA specifically inhibits USP7, 9x, and 10 in PC3 cells (data not shown).
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Our preliminary data suggests that BA specifically inhibits USP7, 9x, and 10 in PC3 cells (data not shown).
23424652
USP7 affects taxane
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USP7 activates taxane. 2 / 2
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In addition, we demonstrated that inhibition of Aurora-A attenuates USP7 mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment.
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High levels of USP7 induced resistance of tumor cells to taxane based chemotherapy.
23348589
USP7 affects substrate
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USP7 activates substrate. 2 / 2
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We observed that inhibition of USP7 alone was not sufficient to induce degradation of substrates , despite USP7 's ability to broadly rescue substrates from degradation .
33417828
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However , inhibition of USP7 alone was not sufficient to promote substrate degradation , suggesting that USP7 functions redundantly with other DUBs .
33417828
USP7 affects pyroptosis
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USP7 activates pyroptosis. 2 / 2
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These data suggest that H2O2 induced ROS production , NLRP3 inflammasome activation , and pyroptosis by increasing USP7 .
33584299
eidos
shUSP7 - or shNC-transduced chondrocytes were treated with either USP7 inhibitor ( P22077 , 5 muM ) or vehicle for 24 h , followed by administration of H2O2 ( 100 muM ) for 24 h. Flow cytometry results showed that H2O2 induced pyroptosis which was blocked by either USP7 KD or USP7 inhibitor ( Figure 2A ) .
33584299
USP7 affects picolinic acid
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USP7 activates picolinic acid. 2 / 2
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Moreover, CHK1 or USP7 silencing with siRNA significantly reduced the number of PLA dots, which demonstrates the specificity of this signal (Fig. 5c).
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Moreover, CHK1 or USP7 silencing with siRNA significantly reduced the number of PLA dots, which demonstrates the specificity of this signal.
32447346
USP7 affects mycn
| 2
USP7 decreases the amount of mycn. 2 / 2
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Moreover, immunohistochemical staining revealed that N-Myc levels are reduced in the Hausp knockout tissues (XREF_FIG); notably, this effect on N-Myc protein levels caused by the Hausp knockout remained the same in the TP53-null background (XREF_FIG).
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As shown in XREF_FIG, reducing HAUSP (RNAi and HAUSP pool) decreased N-Myc protein levels; moreover, the levels of N-Myc were consistently decreased by using each of the four individual oligos composing the HAUSP RNAi pool, excluding off-target effects (XREF_FIG).
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USP7 activates inflammatory response. 2 / 2
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USP7 inhibition has been indicated to limit the inflammatory response in the treatment of acute or chronic inflammation.
33584299
reach
Silencing of USP7 inhibits inflammation and cell apoptosis in ALI mouse.
32440780
USP7 affects WRAP53
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USP7 activates WRAP53. 2 / 2
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Moreover, knockdown of USP7 attenuated the effect of WDR79 on p53, revealing that WDR79 acts as a scaffold protein to affect p53 via USP7.
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Moreover, the data revealed that knockdown of USP7 attenuated the stabilizing effect of WDR79 on Mdm2 and p53.
28406480
USP7 affects Ubiquitination
| 2
eidos
Thus , USP7 regulates NLRP3 inflammasome activation , and chemical inhibition of USP7 by P22077 promotes the ubiquitination level of NLRP3 and blocks inflammasome activation ( Palaz o n-Riquelme et al ., 2018 ) , indicating the multiple roles of USP7 .
33584299
eidos
As described above for PTEN , this ubiquitination is reversed by USP7 ( 143 ) .
20073038
USP7 affects USP47
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USP7 inhibits USP47. 2 / 2
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Due to the multifaceted roles of USP7, many inhibitors have been developed targeting USP7, such as P022077, HBX 41,108, HBX-19,818, HBX-28,258, P5091, Cpd 14 and P22077, in which the latter two molecules also inhibit USP47 [XREF_BIBR - XREF_BIBR].
28031783
reach
Due to the multifaceted roles of USP7, many inhibitors have been developed targeting USP7, such as P022077, HBX 41,108, HBX-19,818, HBX-28,258, P5091, Cpd 14 and P22077, in which the latter two molecules also inhibit USP47.
28279784
USP7 affects USP10
| 1 1
USP7 inhibits USP10. 2 / 2
| 1 1
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Weisberg et al. have performed a phenotypic screen and identified compounds originally discovered for USP7 that inhibit USP10 and induce degradation of the oncogenic kinase FLT3 [ 42 ] .
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Weisberg et al. have performed a phenotypic screen and identified compounds originally discovered for USP7 that inhibit USP10 and induce degradation of the oncogenic kinase FLT3 [ xref ].
30913483
USP7 affects UIMC1
| 2
USP7 inhibits UIMC1. 2 / 2
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As shown in Figure XREF_FIG, knockdown of USP7 partially rescued RAP80 foci, which further supports that inhibition of H2A ubiquitination by HSCARG depends on USP7.
24711370
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As HSCARG depends on USP7 in inhibiting H2A ubiquitination, we then assessed if depletion of USP7 rescued the decreased RAP80 foci caused by ectopic HSCARG.
24711370
USP7 affects PYCARD
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USP7 activates PYCARD. 2 / 2
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In this study, we demonstrated that inhibition of protein deubiquitinase USP7 suppressed osteogenic differentiation of hASCs in a catalytic activity dependent manner, while overexpression of USP7 enhanced hASC osteogenesis.
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Another study found that pharmacological inhibition of USP7 and USP47 prevented the formation of ASC specks and dramatically decreased both IL-18 and IL-1beta release.
33627128
USP7 affects PHF8
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USP7 activates PHF8. 2 / 2
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We showed that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2 and that the interaction between USP7 and PHF8 is augmented during DNA damage.
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Moreover, USP7 promoted PHF8 stabilization conferred cellular resistance to genotoxic insults and was required for the recruitment of BLM and KU70, which are both essential for DNA double-strand break repair.
27183383
USP7 affects NBN
| 2
USP7 inhibits NBN. 2 / 2
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USP7 also disrupted NBs formed from some single PML isoforms, most notably isoforms I and IV.
21305000
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We then investigated whether the USP7 NTD and CTD were sufficient to disrupt the NBs formed from either PML I or PML IV or whether each of these USP7 domains was responsible for regulating one of these PML isoforms.
21305000
USP7 affects MMP13
| 2
USP7 activates MMP13. 2 / 2
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The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1beta and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition.
33584299
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Results also indicated that MIA significantly upregulated USP7, NOX4, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was attenuated by the inhibition of USP7 with P22077 (XREF_FIG).
33584299
USP7 affects MKI67
| 1
USP7 activates MKI67. 1 / 2
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In light of the above findings, we further investigated the mechanism of USP7 induced Ki-67 stabilization in NSCLC cells.
27590858
USP7 affects MDM4
1 | 1
USP7 activates MDM4. 2 / 2
1 | 1
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Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.
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USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy.
32300595
USP7 affects MCL1
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USP7 activates MCL1. 2 / 2
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Deubiquitinase USP7 mediated MCL-1 up-regulation enhances Arsenic and Benzo (a) pyrene co-exposure-induced Cancer Stem Cell like property and Tumorigenesis.
32802178
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Conclusions : The deubiquitinase USP7 mediated MCL-1 up-regulation enhances arsenic and BaP co-exposure-induced CSC like property and tumorigenesis, providing the first evidence demonstrating that USP7 stabilizes MCL-1 protein during the tumorigenic process.
32802178
USP7 affects MAF
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USP7 activates MAF. 2 / 2
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In contrast, another deubiquitinase, USP7, also increased the transcriptional activity of c-Maf, but luciferase activity driven by USP7 was much less affected by mebendazole than luciferase activity driven by USP5.
31197245
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The action of USP7 thus promoted Maf transcriptional activity as evidenced by luciferase assays and by the upregulation of the expression of Maf modulated genes.
31822558
USP7 affects JPT1
| 1 1
USP7 activates JPT1. 2 / 2
| 1 1
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Among these proteins , only HN1 was destabilized by USP7 inhibition .
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Combined inhibition of USP7 and USP14 caused the degradation of HN1, as observed with inhibition of USP7 alone, but also destabilized DBN1, KHLC1, and SVIL, a known USP7 target (XREF_FIG, bottom).
33417828
USP7 affects Interferon
| 1 1
USP7 inhibits Interferon. 2 / 2
| 1 1
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USP7 , in another study , was found to inhibit type I IFN signaling by indirectly targeting TBK1 .
33511009
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USP7, in another study, was found to inhibit type I IFN signaling by indirectly targeting TBK1.
33511009
USP7 affects ITCH
| 2
USP7 inhibits ITCH. 2 / 2
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We found that HAUSP blocked Itch mediated degradation of Gli1 and Spop-Cul3-mediated degradation of Gli2 and Gli3 without affecting Gli mRNA levels.
26120032
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We found that HAUSP blocked Itch mediated degradation of Gli1 and Spop-Cul3-mediated degradation of Gli2 and Gli3 (XREF_FIG, top panels) without affecting Gli mRNA levels (XREF_FIG, bottom panels).
26120032
USP7 affects ING1
| 1
USP7 activates ING1. 1 / 2
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We also find that ING1 physically interacts with herpesvirus associated ubiquitin specific protease (HAUSP), a p53 and MDM2 deubiquitinase (DUB), and knockdown of HAUSP blocks the ability of ING1 to stabilize p53.
21731648
USP7 affects Histone
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USP7 activates Histone. 2 / 2
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The present study evaluated whether USP7 also mediates histone acetyltransferase Tat-interactive protein 60 (Tip60) in the development of ALI inflammation.
32440780
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Although an indirect correlation between USP7 and the metastasis of gastric cancer has been shown previously by altering the levels of USP7 mediated histone demethylase PHF8 (Li et al., 2017), our study demonstrated the direct correlation between USP7 enzyme activity and cancer cell migration ability in a p53 independent manner for the first time.
32922122
USP7 affects GLI3
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USP7 activates GLI3. 2 / 2
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Knockdown of hausp also promoted Gli3 processing in 293T cells (XREF_SUPPLEMENTARY).
26120032
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Knockdown of hausp also promoted Gli3 processing in 293T cells.
26120032
USP7 affects GHR
| 2
USP7 decreases the amount of GHR. 2 / 2
| 2
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While USP7 silencing induced the expression of GHR, GDF8, SCIN, and EHF, silencing MDM2 had no effect on the induction of these genes.
26971997
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While USP7 silencing induced the expression of GHR, GDF8, SCIN and EHF (XREF_SUPPLEMENTARY), silencing MDM2 had no effect on the induction of these genes (XREF_SUPPLEMENTARY).
26971997
USP7 affects ELAVL1
| 2
USP7 activates ELAVL1. 2 / 2
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Finally, HuR knockdown induced a clear decrease in HAUSP levels, emphasizing that HAUSP is a target of HuR (XREF_FIG).
20815019
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Computer analysis of HAUSP mRNA revealed a large 3 ' UTR of 2,000 bp (XREF_FIG upper panel) suggesting that HAUSP could be a target of HuR.
20815019
USP7 affects E1B-55K
| 2
USP7 activates E1B-55K. 2 / 2
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However, during the course of this study, it became clear that USP7 not only specifically targets E1B-55K, but also exerts positive effects on other early proteins (and late proteins).
23555268
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However, considering known functions of USP7 in gene expression control through regulation of histone proteins and the known relationship between adenoviral gene expression activity and the chromatinization of the adenoviral genome inside the nucleus of infected cells, it is also likely that USP7 mediated E1B-55K stability might be exerted through a mechanism other than direct deubiquitination of E1B-55K XREF_BIBR - XREF_BIBR.
23555268
USP7 affects Cyclin
| 2
USP7 activates Cyclin. 2 / 2
| 2
reach
We tested if USP7 can rescue the APC/C substrates cyclin B1 and securin from degradation in mitotic extract.
33417828
reach
We showed that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2 and that the interaction between USP7 and PHF8 is augmented during DNA damage.
27183383
TRAF4 affects USP7
| 1
TRAF4 inhibits USP7. 1 / 2
| 1
reach
Finally, at least one protein, TRAF4, negatively regulates USP7 activity.
30807924
TNF affects USP7
| 2
TNF activates USP7. 2 / 2
| 2
reach
Nonetheless, a minimum of two siRNA molecules led to increased levels of nuclear NF-kappaB in A549 cells depleted of A20, USP7, USP49, USP54, or FBXO36 and treated with TNF for 120min.
25071782
reach
Furthermore, the interaction between endogenous HSCARG and USP7 in cells treated with or without TNFalpha was investigated by co-IP assay.
24832601
RNA interference affects USP7
| 2
RNA interference inhibits USP7. 2 / 2
| 2
eidos
As may be expected , partial reduction of USP7 levels by RNA interference ( RNAi ) was shown to destabilize p53 ( Li et al ., 2004 ) .
17291557
eidos
Partial reduction of USP7 activity by RNAi destabilizes p53 through reduced deubiquitination .
17291557
RAG2 affects USP7
| 2
RAG2 inhibits USP7. 2 / 2
| 2
reach
UCHL1, UCHL3, USP2 and USP8 were found to be inhibited by AM146, RA-9, and RA-14, which did not inhibit Ataxin-3, A20, BAP1, Otubain 1 or USP7.
28279784
reach
UCHL1, UCHL3, USP2 and USP8 were found to be inhibited by AM146, RA-9, and RA-14 which did not inhibit Ataxin-3, A20, BAP1, Otubain 1 or USP7 [XREF_BIBR].
28031783
POSTN affects USP7
| 2
POSTN inhibits USP7. 2 / 2
| 2
reach
PN suppresses the activity of ubiquitin specific peptidase 7 (USP7) and WNT and beta-catenin signaling [XREF_BIBR].
32823992
reach
PN suppresses the activity of ubiquitin specific peptidase 7 (USP7) and WNT and beta-catenin signaling [63].
32823992
PNLIP affects USP7
| 2
PNLIP inhibits USP7. 2 / 2
| 2
reach
In summary, our findings reveal that PTL inhibits USP7 activity, identifying a potential mechanism by which PTL suppresses Wnt and beta-catenin signaling.
32029476
reach
Here, we report that sesquiterpene lactone parthenolide (PTL) inhibits USP7 activity, assessed with deubiquitinating enzyme activity assays, including fluorogenic Ub-AMC and Ub-Rho 110, Ub-VME/PA labeling and Di-Ub hydrolysis assays.
32029476
NOX4 affects USP7
| 2
NOX4 activates USP7. 2 / 2
| 2
reach
The inhibition of NOX4 blocked the pro OA effect of USP7.
33584299
reach
Inhibition of NOX4 Blocked the Effect of USP7 on Pyroptosis, ROS Production, and NLRP3 Inflammasome Activation.
33584299
NCIT:C94600 affects USP7
| 2
NCIT:C94600 activates USP7. 2 / 2
| 2
sparser
Since FoxOs localization is also regulated by mono-ubiquitination [ xref ] and that BCR-ABL activates the FoxOs-deubiquitinase HAUSP [ xref ], it could be speculated that FoxOs nuclear localization could be affected by BCR-ABL/PML/HAUSP network in a similar manner as for PTEN [ xref ].
27184141
sparser
Recently, it was observed that BCR-ABL activates the deubiquitinase HAUSP to promote phosphatase and tensin homolog (PTEN) delocalization in CML ( xref ).
27899971
reach
Further, downregulation of SUV39H1 protein expression in response to USP7 silencing was inhibited when cells were treated with the proteasomal inhibitor MG-132.
26971997
reach
Next, addition of MG132, a proteasome specific inhibitor, effectively blocked the reduction of USP7 associated with ECT2 depletion, suggesting that this effect was probably through a proteasome mediated protein degradation mechanism.
32929379
MIR15B affects USP7
| 2
MIR15B inhibits USP7. 2 / 2
| 2
eidos
Moreover , bioinformatics analysis and dual-luciferase reporter gene assay in combination validated that miR-15b could target USP7 and suppresses USP7 expression .
33434305
eidos
Combining previous studies with our results , a regulatory network could be proposed in the antagonizing atherosclerosis progression that depletion of miR-15b promoted USP7 expression to up-regulate KDM6B .
33434305
INS affects USP7
| 2
INS activates USP7. 2 / 2
| 2
reach
We also performed pull-down analysis using the MATH domain of USP7 as a bait and IRS-2 derived from H4IIE cells treated with or without insulin as a prey.
22634009
reach
We also demonstrate that insulin or IGF-I treatment stimulates USP7 dissociation from IRSs via activation of PI3K pathway, leading to degradation of IRSs.
22634009
HBX 41108 affects USP7
1 | 1
HBX 41108 inhibits USP7. 2 / 2
1 | 1
reach
HBX 41108 was discovered to inhibit USP7 activity at a submicromolar range.
29415985
tas
No evidence text available
23684893
EZH2 affects USP7
| 2
EZH2 activates USP7. 2 / 2
| 2
reach
Herein, we identified that EZH2 is a deubiquitination target of USP7 and that EZH2 protein stability is increased by USP7.
32453339
reach
To further address the regulatory mechanism underlying EZH2 protein stabilization by USP7, we examined whether EZH2 is a deubiquitination target of USP7.
32453339
E3_Ub_ligase affects USP7
| 2
E3_Ub_ligase activates USP7. 2 / 2
| 2
reach
Taking these data together, USP7 beta represents a higher MW species of USP7 that shares significant amino acid homology.ICP0 can catalyse the ubiquitination of USP7 (Boutell et al., 2005), suggesting[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
18590780
reach
The inductive effect of TSPY1 on the ubiquitination of USP7 prompted a preliminary exploration of the influence of TSPY1 on the expression of thyroid hormone receptor interactor 12 (TRIP12), a newly confirmed E3 ubiquitin ligase targeting USP7 (ref.
29748603
CI affects USP7
| 2
CI increases the amount of USP7. 2 / 2
| 2
reach
Compared with control discs, knockdown of usp7 downregulated Ci FL levels in A-compartment cells near the A/P boundary, but did not affect ci transcription as shown by the expression of ci-lacZ, an en[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
26120032
reach
Compared with control discs (XREF_FIG), knockdown of usp7 downregulated Ci FL levels in A-compartment cells near the A/P boundary (XREF_FIG), but did not affect ci transcription as shown by the expression of ci-lacZ, an enhancer trap that mimics ci transcription (XREF_SUPPLEMENTARY), indicating that Usp7 may affect Ci through regulating Ci protein stability.
26120032
CDK1 affects USP7
| 2
CDK1 inhibits USP7. 2 / 2
| 2
reach
Our work reveals that USP7 limits CDK1 activity at all cell cycle stages, providing a novel mechanism that explains the toxicity of USP7 inhibitors through untimely activation of CDK1.
33856059
reach
USP7 limits CDK1 activity throughout the cell cycle.
33856059
Phenethyl isothiocyanate inhibits USP7. 1 / 1
| 1
reach
As shown above, BITC and PEITC do not inhibit USP7, which explains the resistance of these cells.
26542215
Phenethyl isothiocyanate decreases the amount of USP7.
1 |
Phenethyl isothiocyanate decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
17616710
Nigericin affects USP7
| 1 1
Nigericin inhibits USP7.
| 1
Nigericin inhibits USP7. 1 / 1
| 1
reach
At the concentration used in this experiment, we observed that P22077 did not cause a complete inhibition of the nigericin induced increase in activity of USP7 and USP47 that may be due to the irreversible action of the ABP versus the reversible inhibitor 24.
30206189
Nigericin activates USP7.
| 1
Nigericin activates USP7. 1 / 1
| 1
sparser
Nigericin‐induced activation of both USP7 and USP47 was not dependent on LPS priming (Fig xref A, final lane).
30206189
Lipopolysaccharide, E coli O55-B5 increases the amount of USP7.
1 |
Lipopolysaccharide, E coli O55-B5 increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28134560
Lipopolysaccharide, E coli O55-B5 decreases the amount of USP7.
1 |
Lipopolysaccharide, E coli O55-B5 decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28134560
Flutamide affects USP7
2 |
Flutamide increases the amount of USP7.
1 |
Flutamide increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
24136188
Flutamide decreases the amount of USP7.
1 |
Flutamide decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
21525395
Copper(II) sulfate affects USP7
2 |
Copper(II) sulfate increases the amount of USP7.
1 |
Copper(II) sulfate increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
19789285
Copper(II) sulfate decreases the amount of USP7.
1 |
Copper(II) sulfate decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
19789285
Chloroquine affects USP7
2 |
Chloroquine increases the amount of USP7.
1 |
Chloroquine increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28134560
Chloroquine decreases the amount of USP7.
1 |
Chloroquine decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28134560
Aflatoxin B1 affects USP7
2 |
Aflatoxin B1 increases the amount of USP7.
1 |
Aflatoxin B1 increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
19770486
Aflatoxin B1 decreases the amount of USP7.
1 |
Aflatoxin B1 decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
21641981
ZEB1 affects USP7
| 2
ZEB1 activates USP7. 1 / 1
| 1
reach
How exactly ZEB1 specifically promotes the interaction of USP7 with CHK1 but not with other USP7 substrates warrants future investigation.
25086746
ZEB1 bound to elaD activates USP7. 1 / 1
| 1
reach
ZEB1 interacts with deubiquitinase, ubiquitin specific peptidase 7 (USP7) and promotes the deubiquitination ability of USP7 and then stabilizes CHK1 (XREF_FIG).
32426267
USP7 increases the amount of p-tolyl beta-D-glucuronide.
| 1
USP7 increases the amount of p-tolyl beta-D-glucuronide. 1 / 1
| 1
reach
Histone deubiquitination has been the subject of recent reviews [XREF_BIBR, XREF_BIBR, XREF_BIBR], and here we highlight three DUBs, USP7, USP16, and BAP1, that function in polycomb group (PcG) complexes and modulate transcription of PcG target genes.
23845989
reach
Given the precedents in Drosophila, we initially thought that human USP7 might be contributing to PcG mediated silencing by reversing the mono-ubiquitination of histone H2B.
20601937
USP7 affects glucose
| 2
USP7 inhibits glucose. 1 / 1
| 1
reach
In vivo analysis using adenoviruses confirmed that HAUSP, but not the HAUSP C223S mutant, decreased blood glucose and triglyceride levels, which are associated with the increased expression of endogenous PPARgamma and lipid accumulation in the liver.
24072712
USP7-C223S inhibits glucose. 1 / 1
| 1
reach
In vivo analysis using adenoviruses confirmed that HAUSP, but not the HAUSP C223S mutant, decreased blood glucose and triglyceride levels, which are associated with the increased expression of endogenous PPARgamma and lipid accumulation in the liver.
24072712
USP7 affects elaD
| 2
USP7 inhibits elaD.
| 1
USP7 inhibits elaD. 1 / 1
| 1
reach
By contrast, in pediatric cancer the majority of the USP7 mutations identified are loss-of-function mutations including frame shift mutations within the catalytic domain that would encode truncated USP7 proteins and missense mutations that have reduced deubiquitinase activity.
24710217
USP7 activates elaD.
| 1
USP7 activates elaD. 1 / 1
| 1
reach
Here we present structural, biochemical, and biophysical analyses elucidating the molecular mechanism by which the C-terminal 19 amino acids of USP7 (residues 1084-1102) enhance the ubiquitin cleavage activity of the deubiquitinase (DUB) domain.
27452404
USP7 affects TWIST1
| 2
USP7-K444R activates TWIST1. 1 / 1
| 1
reach
Western blot analysis showed that mouse Twist1, Vegf and Glut1 proteins were not induced by hypoxia in Hausp K444R fibroblasts (XREF_FIG).
27934968
USP7 activates TWIST1. 1 / 1
| 1
reach
To substantiate the in vivo stabilization of HIF-1alpha by HAUSP, a transient co-transfection experiment showed that overexpression of HAUSP increased HIF-1alpha at the protein levels but not the mRNA levels (XREF_FIG and XREF_SUPPLEMENTARY), and further activated a Twist1 promoter driven reporter construct (XREF_FIG) XREF_BIBR.
27934968
USP7 affects TRAF
| 2
USP7 inhibits TRAF.
| 1
USP7 inhibits TRAF. 1 / 1
| 1
reach
We confirmed USP7 suppression of TRAF mediated innate immune signaling in an assay employing transfected, overexpressed mitochondrial antiviral signaling protein (MAVS), an effector of signaling initiated by retinoic acid inducible gene I (RIG-I)-like receptors and functioning through TRAFs, and a cotransfected IFN-beta-luciferase reporter (XREF_FIG).
31666375
USP7 activates TRAF.
| 1
USP7 activates TRAF. 1 / 1
| 1
reach
USP7 modulation of TRAF signaling.
31666375
USP7 affects TCF12
| 2
USP7 inhibits TCF12.
| 1
USP7 inhibits TCF12. 1 / 1
| 1
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These experiments showed that USP7 haploinsufficiency decreases the E protein activity of E2A and HEB and promotes T-ALL cell growth.
33664368
USP7 activates TCF12.
| 1
USP7 activates TCF12. 1 / 1
| 1
reach
Down-regulation of E2A and HEB targets by USP7 haploinsufficiency, evident in the analysis of patient T-ALL samples and shRNA knock-down in T-ALL cell lines, prompted us to evaluate whether USP7 forms a co and regulatory complex with TAL1, E2A, and HEB.
33664368
USP7 affects SOCS1
| 2
USP7 inhibits SOCS1.
| 1
USP7 inhibits SOCS1. 1 / 1
| 1
reach
USP7 Small-molecule Inhibitors Enhance Type I-Interferon Antiviral Efficacy by Destabilizing SOCS1.
31691271
USP7 increases the amount of SOCS1.
| 1
USP7 increases the amount of SOCS1. 1 / 1
| 1
reach
Importantly, USP7 small-molecule inhibitors, P5091 and P22077, inhibit SOCS1 expression and enhance IFN-I antiviral efficacy.
31691271
USP7 affects NOX4
| 2
USP7 decreases the amount of NOX4.
| 1
USP7 decreases the amount of NOX4. 1 / 1
| 1
reach
Western blots showed that USP7 KD or P22077 treatment significantly inhibited H 2 O 2 -induced USP7 and NOX4 protein expressions (XREF_FIG).
33584299
USP7 activates NOX4.
| 1
USP7 activates NOX4. 1 / 1
| 1
reach
Co-IP results showed that USP7 interacted with NOX4, and USP7 KD enhanced NOX4 ubiquitinylation.
33584299
USP7 affects NFE2L1
| 2
USP7 increases the amount of NFE2L1.
| 1
USP7 increases the amount of NFE2L1. 1 / 1
| 1
reach
Loss of USP7 function attenuated the induction of Nrf1 protein expression in response to treatment with arsenic and other toxic metals, and inhibition of USP7 activity significantly sensitized cells to arsenic treatment.
33933455
USP7 activates NFE2L1.
| 1
USP7 activates NFE2L1. 1 / 1
| 1
reach
Collectively, these findings suggest that USP7 may act to modulate abundance of Nrf1 protein to induce gene expression in response to toxic metal exposure.
33933455
USP7 affects NEK2
| 2
USP7 inhibits NEK2.
| 1
USP7 inhibits NEK2. 1 / 1
| 1
reach
Furthermore, overexpression of USP7 reduced the half-life of NEK2, supporting the concept that USP7 enhances NEK2 stability.
33754007
USP7 activates NEK2.
| 1
USP7 activates NEK2. 1 / 1
| 1
reach
Furthermore, overexpression of USP7 reduced the half-life of NEK2, supporting the concept that USP7 enhances NEK2 stability.
33754007
USP7 affects MARCHF7
| 2
USP7 inhibits MARCHF7.
| 1
USP7 inhibits MARCHF7. 1 / 1
| 1
reach
Decreasing axotrophin auto-ubiquitination by overexpression of ubiquitin hydrolases USP7 and USP9x increased the axotrophin level XREF_BIBR.
24905733
USP7 activates MARCHF7.
| 1
USP7 activates MARCHF7. 1 / 1
| 1
reach
Furthermore, DUBs are known to regulate stability of only 4 of these proteins, including the ubiquitin ligases MARCH7 and BIRC3, which are targeted by USP7 or USP9 and USP19, respectively.
33417828
USP7 affects MAPK
| 2
USP7 bound to IKBKG inhibits MAPK. 1 / 1
| 1
reach
In the presence of ICP0, however, it interacts with ICP0 and translocates to the cytoplasm where USP7 binds and deubiquitinates TRAF6 and IKKgamma, thereby inhibiting NF-kappaB and MAPK activation.
24262390
USP7 bound to TRAF6 inhibits MAPK. 1 / 1
| 1
reach
In the presence of ICP0, however, it interacts with ICP0 and translocates to the cytoplasm where USP7 binds and deubiquitinates TRAF6 and IKKgamma, thereby inhibiting NF-kappaB and MAPK activation.
24262390
USP7 affects IL2
| 2
USP7 inhibits IL2.
| 1
USP7 inhibits IL2. 1 / 1
| 1
reach
Although cotransfection of Foxp3 Del250 with USP7 alone did not influence IL2 reporter activity, USP7 significantly increased IL2 promoter repression mediated by WT Foxp3.
23973222
USP7 decreases the amount of IL2.
| 1
USP7 decreases the amount of IL2. 1 / 1
| 1
reach
USP7 knockout enhances IL-2 expression in PBMC cells (XREF_FIG E).
33777676
USP7 affects IFNB1
| 2
USP7 inhibits IFNB1. 1 / 1
| 1
reach
Overexpression of USP7 suppressed Sendai virus and polyinosinic-polycytidylic acid and poly (deoxyadenylic-deoxythymidylic)-induced ISRE and IFN-beta activation, and enhanced virus replication.
29688809
USP7 bound to TRIM27 inhibits IFNB1. 1 / 1
| 1
reach
In SeV infection there seems to be another mechanism at work; the ubiquitin-specific peptidase 7 (USP7) interacts with and stabilizes TRIM27, promoting the degradation of TBK1 and suppressing the activation of IFN-β (Cai et al., 2018) .
34925304
USP7 affects ICP0
| 2
USP7 decreases the amount of ICP0.
| 1
USP7 decreases the amount of ICP0. 1 / 1
| 1
reach
Likewise, depletion of USP7 by RNA interference (RNAi) has also been shown to decrease the stability and expression levels of ICP0 during infection [XREF_BIBR, XREF_BIBR].
21765858
USP7 activates ICP0.
| 1
USP7 activates ICP0. 1 / 1
| 1
reach
USP7 also contributes to ICP0 induced reactivation of gene expression from integrated adeno-associated virus AAV [30].
18817868
USP7 affects DNA methylation
| 1 1
USP7 inhibits DNA methylation.
| 1
eidos
The diagrams illustrate how USP7 suppresses excessive DNA methylation by DNMT1 to promote DNA methylation homeostasis .
32884836
USP7 activates DNA methylation.
| 1
USP7 bound to DNMT1 activates DNA methylation. 1 / 1
| 1
reach
The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1.
29056421
USP7 affects DHX40
| 2
USP7 increases the amount of DHX40. 1 / 1
| 1
reach
The results show that the levels of DDX24 and DHX40 were greatly decreased by USP7 silencing in both cell lines and that these levels were restored with MG132 treatment.
30367141
Modified USP7 increases the amount of DHX40. 1 / 1
| 1
reach
Overexpression of WT USP7, but not the C223S catalytically inactive mutant of USP7, was found to increase the levels of DDX24, DHX40 and USP11.
30367141
USP7 affects DDX24
| 2
Modified USP7 increases the amount of DDX24. 1 / 1
| 1
reach
Overexpression of WT USP7, but not the C223S catalytically inactive mutant of USP7, was found to increase the levels of DDX24, DHX40 and USP11.
30367141
USP7 increases the amount of DDX24. 1 / 1
| 1
reach
The results show that the levels of DDX24 and DHX40 were greatly decreased by USP7 silencing in both cell lines and that these levels were restored with MG132 treatment.
30367141
USP7 affects Carcinogenesis
| 2
USP7 inhibits Carcinogenesis.
| 1
eidos
It is critical for several important functions in the cell , and therefore dysregulation of USP7 can contribute to tumorigenesis .
33650720
USP7 activates Carcinogenesis.
| 1
USP7 activates Carcinogenesis. 1 / 1
| 1
eidos
Also , USP7 regulates PTEN localization and eventually inducing tumorigenesis .
33165832
USP7 affects CLU
| 2
USP7 increases the amount of CLU.
| 1
USP7 increases the amount of CLU. 1 / 1
| 1
reach
USP7 then stabilizes the expression of JMJD3 and promotes the expression of CLU by binding to the CLU promoter region, inducing tumorigenesis and progression of EC.
33768140
USP7 decreases the amount of CLU.
| 1
USP7 decreases the amount of CLU. 1 / 1
| 1
reach
Additionally, JMJD3 and CLU expression was not increased by knockdown of USP7 in the FOXO6 overexpressed cells, whereas CLU expression was decreased by knockdown of JMJD3, and USP7 expression could still be regulated by FOXO6 simultaneously.
33768140
USP7 affects BAX
| 2
USP7 inhibits BAX.
| 1
USP7 inhibits BAX. 1 / 1
| 1
reach
Disruption of USP7 function results in dis-regulated several key biological processes and subsequently activates BAX.
32002017
USP7 decreases the amount of BAX.
| 1
USP7 decreases the amount of BAX. 1 / 1
| 1
reach
A recent study has shown that inhibition of USP7 increases the Bax protein level in the MCF7 cell line, which harbors wild-type p53 protein (Xia at al., 2019).
32922122
USP7 affects APC
| 2
USP7 inhibits mutated APC. 1 / 1
| 1
reach
In summary, USP7 inhibition by CRISPR targeting or treatment with two different small molecules consistently suppresses aberrant Wnt activation in CID-loss APC mutant cells.
29045831
USP7 inhibits APC. 1 / 1
| 1
reach
USP7 Depletion Significantly Inhibits APC Mutated CRC Tumor Growth InVivo.
29045831
USP7 affects AKT
| 2
USP7 increases the amount of AKT.
| 1
USP7 increases the amount of AKT. 1 / 1
| 1
reach
However, our results show that USP7 knockdown decreases the expression levels of MDM2, AKT, and NF-kappaB genes without being dependent on p53 protein.
32922122
USP7 activates AKT.
| 1
USP7 activates AKT. 1 / 1
| 1
reach
Moreover, USP7 siRNA blocked the activation of Akt/ERK signaling pathway.
34812471
TRIP12 affects USP7
| 2
TRIP12 inhibits USP7.
| 1
TRIP12 inhibits USP7. 1 / 1
| 1
reach
68 On another hand, overexpression of TRIP12 (R SILAC = 1.62) produces inhibition of USP7, which is an ubiquitin specific processing protease whose depletion induce cell cycle arrest at the S phase.
30806414
TRIP12 activates USP7.
| 1
TRIP12 activates USP7. 1 / 1
| 1
reach
Interestingly, USP7 itself is also targeted by TRIP12 for proteasomal degradation, indicating that they are mutual substrates for each other [XREF_BIBR].
29858610
SUMO1 affects USP7
| 2
SUMO1 inhibits USP7.
| 1
SUMO1 inhibits USP7. 1 / 1
| 1
reach
Proteomic and immunoprecipitation analyses further reveal that the SIM3 motif is required for the EBNA1 mediated inhibitory effects on SUMO2 modified STUB1, SUMO2 mediated degradation of USP7, and SUMO1 modified KAP1.
32176739
SUMO1 activates USP7.
| 1
SUMO1 activates USP7. 1 / 1
| 1
reach
In two DNMT1 complexes, both of the 2nd modes display the large displacement of partner proteins, especially for the UBL1–2 module of USP7, which enjoyed the largest flexibility.
34500587
Proteasome affects USP7
| 2
Proteasome inhibits USP7.
| 1
Proteasome inhibits USP7. 1 / 1
| 1
reach
Taken together, these data indicate that ICP0 can interact with and promote the proteasome dependent degradation of both USP7 and USP7 beta during HSV-1 infection.ICP0 belongs to the RING-finger class[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
18590780
Proteasome decreases the amount of USP7.
| 1
Proteasome decreases the amount of USP7. 1 / 1
| 1
reach
36 Of note, our data revealed that inhibition of proteasome up-regulated expression of USP7 and KDM6B, while increased USP7 expression promoted osteoblast differentiation and autophagy, alleviating osteoporosis.
33434305
HUWE1 affects USP7
| 2
HUWE1 increases the amount of USP7.
| 1
HUWE1 increases the amount of USP7. 1 / 1
| 1
reach
Further experiments showed that knockdown of HectH9 significantly decreased the K63 polyubiquitination HAUSP levels compared to the control or TRAF6 knockdown (XREF_SUPPLEMENTARY).
27934968
HUWE1 activates USP7.
| 1
HUWE1 activates USP7. 1 / 1
| 1
reach
Finally, as HIF-1alpha plays a major role in inducing tumor progression [XREF_BIBR], K63 polyubiquination of HAUSP mediated by HUWE1 would contribute to the oncogenic function of HUWE1.
30176860
FOXP3 affects USP7
| 2
FOXP3 increases the amount of USP7.
| 1
Ubiquitinated FOXP3 increases the amount of USP7. 1 / 1
| 1
reach
Control of ubiquitination of the FOXP3 protein by enhancing its acetylation (HDAC inhibition, p300 induction), inhibiting cytokine-induced Stub1 levels and enhancing USP7 expression, prevents FOXP3 degradation.
34224053
FOXP3 decreases the amount of USP7.
| 1
FOXP3 decreases the amount of USP7. 1 / 1
| 1
reach
Second, analysis of published databases showed that of various Usp genes, expression of Usp7 in particular was markedly decreased by Foxp3 ablation in murine Tregs.
27769803
Zinc dichloride affects USP7
1 |
Zinc dichloride decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
16973896
Valproic acid affects USP7
1 |
Valproic acid decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28001369
VIRF-3 affects USP7
| 1
VIRF-3 activates USP7. 1 / 1
| 1
reach
Here, we identify ubiquitin specific protease 7 (USP7) deubiquitinase targeting by vIRF-3 (in addition to previously reported USP7 binding by vIRF-1 and vIRF-4), the importance of vIRF-1 and vIRF-3 interactions with USP7 for latent PEL cell growth and viability, and the positive and negative contributions, respectively, of USP7 targeting by vIRF-1 and vIRF-3 to HHV-8 productive replication.
29343584
VIRF-1 affects USP7
| 1
VIRF-1 activates USP7. 1 / 1
| 1
reach
Here, we identify ubiquitin specific protease 7 (USP7) deubiquitinase targeting by vIRF-3 (in addition to previously reported USP7 binding by vIRF-1 and vIRF-4), the importance of vIRF-1 and vIRF-3 interactions with USP7 for latent PEL cell growth and viability, and the positive and negative contributions, respectively, of USP7 targeting by vIRF-1 and vIRF-3 to HHV-8 productive replication.
29343584
Tungsten affects USP7
1 |
Tungsten decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
30912803
Troglitazone affects USP7
1 |
Troglitazone decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28973697
Trans-pinosylvin affects USP7
1 |
Trans-pinosylvin increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
23333577
Topotecan affects USP7
1 |
Topotecan decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
25729387
Thiol-dependent ubiquitin-specific protease activity inhibits USP7. 1 / 1
| 1
eidos
Thus , our data revealed that loss of USP7 variably reduced DNMT1 and UHRF1 protein stability , presumably due to its deubiquitinase activity toward DNMT1 and UHRF1 as reported previously38-41 .
32884836
Sunitinib affects USP7
1 |
Sunitinib increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
31533062
Sirtinol affects USP7
1 |
Sirtinol increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
25665036
Resveratrol affects USP7
1 |
Resveratrol increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
25665036
Protein affects USP7
| 1
Protein activates USP7. 1 / 1
| 1
eidos
Consistent with this idea , other proteins can mediate USP7 association with p5353 .
32985545
Phlorizin affects USP7
1 |
Phlorizin decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
22538082
Paraquat affects USP7
1 |
Paraquat decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
21371552
Palbociclib affects USP7
| 1
Palbociclib activates USP7. 1 / 1
| 1
reach
PD0332991 triggers the dissociation of HAUSP from MDM2.
25803170
Paclitaxel affects USP7
| 1
Paclitaxel activates USP7. 1 / 1
| 1
reach
There is a study that suggested that cisplatin and paclitaxel promote miR-522 secretion from cancer-associated fibroblasts by activating the USP7/hnRNPA1 axis, leading to arachidonate lipoxygenase 15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately resulting in decreased chemo-sensitivity [37].
| PMC
PORF45 affects USP7
| 1
PORF45 activates USP7. 1 / 1
| 1
reach
One consequence of USP7 targeting by pORF45 is the stabilization of another tegument protein, specified by ORF33, through complexing and effective recruitment of USP7 activity to pORF33, resulting in protease mediated removal of K48 linked polyubiquitin adducts and thereby rescue from proteasomal degradation.
31666375
Oxaliplatin affects USP7
1 |
Oxaliplatin decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
25729387
Nefazodone affects USP7
1 |
Nefazodone increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
24136188
Mitochondrial DNA damage affects USP7
1 |
Mitochondrial DNA damage decreases the amount of USP7. 1 / 1
1 |
bel
To better understand the consequences of mtDNA deletions, we microarrayed six cell types containing mtDNA deletions from KSS and CPEO patients. Indicated are transcripts shared and downregulated in cells harboring mtDNA deletions in >3 experiments (Table 4); Differentially expressed genes were identified by comparing GeneChips designated as baseline (muscles, myoblasts, fibroblasts, and lymphoblasts from healthy subjects, fusion control cell lines, and parental 143B cells) with the ones that represent the experimental parameters (muscles, myoblasts, fibroblasts, and lymphoblasts from patients, mutant cybrids, and 143B rho zero cells) using a difference in mean fluorescence ? 30 and a P value < 0.05; 37 downregulated genes; 26 upregulated genes;
17157191
Methylmercury compound decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
26558463
Methylmercury chloride decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28001369
Metformin affects USP7
| 1
Metformin inhibits USP7. 1 / 1
| 1
reach
Metformin is primarily used to regulate AMPK-mTOR signaling, inhibits HAUSP activity and enhances growth inhibition in cancer cells.
29967688
LanA1 affects USP7
| 1
LanA1 activates USP7. 1 / 1
| 1
reach
USP7 targeting by LANA appears to inhibit DNA replication, a phenomenon mirroring the situation reported for the functionally equivalent EBNA1 latency protein of Epstein-Barr virus.
31666375
Jinfukang affects USP7
1 |
Jinfukang decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
27392435
Indometacin affects USP7
1 |
Indometacin increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28628672
Hsa-miR-935 affects USP7
1 |
Hsa-miR-935 decreases the amount of USP7. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23622248
Hsa-miR-877-3p affects USP7
1 |
Hsa-miR-877-3p decreases the amount of USP7. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23622248
Hsa-miR-615-3p affects USP7
1 |
Hsa-miR-615-3p decreases the amount of USP7. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23622248
Hsa-miR-3676-3p affects USP7
1 |
Hsa-miR-3676-3p decreases the amount of USP7. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23622248
Hsa-miR-26a-5p affects USP7
1 |
Hsa-miR-26a-5p decreases the amount of USP7. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
23622248
Hsa-miR-21-5p affects USP7
1 |
Hsa-miR-21-5p decreases the amount of USP7. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
18591254
Hsa-miR-16-5p affects USP7
1 |
Hsa-miR-16-5p decreases the amount of USP7. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
18668040
Hexabromocyclododecane increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
29177809
Gentamycin affects USP7
1 |
Gentamycin increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
22061828
Formaldehyde affects USP7
1 |
Formaldehyde decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
23649840
Fenofibrate affects USP7
1 |
Fenofibrate increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
21318169
Ethyl methanesulfonate decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
23649840
Equilenin affects USP7
1 |
Equilenin increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
25611945
Enzyme inhibitor affects USP7
1 |
ctd
No evidence text available
23301498
Emodin affects USP7
| 1
Emodin activates USP7. 1 / 1
| 1
reach
To rule out the possibility that residual CK2alpha remaining after silencing was sufficient to bring about USP7 induced PML-NB disruption, we assessed the effect of USP7 and C223S on PML-NBs in CNE2 cells treated with emodin, an inhibitor of CK2 catalytic activity (XREF_FIG).
21305000
Dimethylarsinic acid increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
17720352
Dimethyl-4-toluidine decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
27638505
Dimethyl sulfoxide affects USP7
| 1
Dimethyl sulfoxide increases the amount of USP7. 1 / 1
| 1
reach
Western blot analysis found that compared with oe-NC and DMSO treatment, both MG132+ oe-NC and oe-USP7+ DMSO treatment increased USP7 and KDM6B protein expression, while combined treatment of oe-USP7 and MG132 resulted in even higher KDM6B and USP7 protein level in osteoblasts (P <.05).
33434305
Diethanolamine affects USP7
1 |
Diethanolamine increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
20537412
Dibutyl phthalate affects USP7
1 |
Dibutyl phthalate decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
21266533
Diarsenic trioxide affects USP7
| 1
Diarsenic trioxide inhibits USP7 bound to MDM2 and DAXX. 1 / 1
| 1
trips
Trisenox Disrupts MDM2-DAXX-HAUSP Complex and Induces Apoptosis in a Mouse Model of Acute Leukemia.
32489456
Dexamethasone affects USP7
1 |
Dexamethasone increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
28628672
Cytarabine affects USP7
1 |
Cytarabine decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
19194470
Cyanoginosin LR affects USP7
1 |
Cyanoginosin LR decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
26984711
Cocaine affects USP7
1 |
Cocaine increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
17898221
Clofibrate affects USP7
1 |
Clofibrate decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
17585979
Chloroprene affects USP7
1 |
Chloroprene increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
23125180
Chase affects USP7
| 1
Chase activates USP7. 1 / 1
| 1
reach
The stabilizing effect of USP7 upon E1B-55K was further supported by cycloheximide chase assays demonstrating a reduced half-life of E1B-55K in the USP7 knockdown background (XREF_SUPPLEMENTARY) and after HBX or HBX41108 treatment (XREF_SUPPLEMENTARY).
23555268
Cell affects USP7
| 1
Cell inhibits USP7. 1 / 1
| 1
eidos
As indicated in Fig. 2B , when cells were treated with Almac4 to inhibit USP7 activity , expression of PD-L1 was decreased in both of the two cell lines in a time-dependent manner ( Fig. 2B ) .
33777676
Carbonyl sulfide affects USP7
1 |
Carbonyl sulfide increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
19395590
Carbon nanotube affects USP7
1 |
Carbon nanotube decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
25554681
Cadmium dichloride affects USP7
1 |
Cadmium dichloride decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
16973896
Butanal affects USP7
1 |
Butanal decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
26079696
reach
As shown above, BITC and PEITC do not inhibit USP7, which explains the resistance of these cells.
26542215
Benzo[a]pyrene diol epoxide I decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
19150397
Bathocuproine disulfonic acid decreases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
16973896
Arsenous acid affects USP7
| 1
Arsenous acid activates USP7. 1 / 1
| 1
reach
To determine whether USP7 is important for arsenic induced degradation of PML, CNE2 cells were transfected with siRNA against GFP or USP7 in quadruplicates and two of each sample were treated with arsenic trioxide (XREF_FIG).
21305000
Apocynin affects USP7
| 1
Apocynin decreases the amount of USP7. 1 / 1
| 1
reach
ELISA and Western blotting results indicated that USP7 overexpression significantly increased IL-1beta and IL-18 levels as well as the expression of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was decreased by USP7 KD or apocynin (XREF_FIG).
33584299
Amide affects USP7
| 1
Amide inhibits USP7. 1 / 1
| 1
reach
Similarly, removal of the amide carbonyl, as in 4, abrogated USP7 activity as did contraction of the 6-membered piperidine to a 5-membered ring (5).
29056421
X affects USP7
| 1
X inhibits USP7. 1 / 1
| 1
reach
Moreover, in order to investigate whether USP7 inhibition leads to effects similar to USP7 knockdown, infected H1299 and A549 cells were subsequently treated with inhibitor HBX.
23555268
Wnt affects USP7
| 1
Wnt activates USP7. 1 / 1
| 1
sparser
Transient targeting of USP7 in SW480 cells showed robust suppression of USP7 protein and Wnt activation, while the USP7-depleted cells were rapidly lost upon passaging and colony picking ( xref E and S4F).
29045831
Viruses affects USP7
| 1
Viruses inhibits USP7. 1 / 1
| 1
eidos
One reason why the virus could promote degradation of USP7 is because it has a major role in TLR - and TNFa receptor ( TNFR ) - induced gene expression [ 145 ] .
33374862
USP7 affects villin
| 1
Modified USP7 increases the amount of villin. 1 / 1
| 1
reach
Overexpression of HAUSP significantly increased villin mRNA level, but the other proteins (nucleolin, PKM2, ANXA1, and PP2A) did not show any significant change in their transcriptional levels (XREF_SUPPLEMENTARY).
25695607
USP7 affects vhp-1
| 1
USP7 increases the amount of vhp-1. 1 / 1
| 1
reach
We identified that knockdown of math-33, the homolog of mammalian USP7, decreased VHP-1 levels.
33674585
USP7 affects toll-like receptor
| 1
reach
It has also been reported that ICP0 can translocate USP7 from the nucleus to the cytosol, where USP7 in complex with ICP0 attenuates the toll like receptor (TLR) regulated immune response by deubiquitinating TRAF6 and IKKgamma (also known as NEMO) [XREF_BIBR].
26046769
USP7 affects tat
| 1
USP7 activates tat. 1 / 1
| 1
reach
As expected, deletion of the USP7 gene using the CRISPR-Cas9 method reduced the Tat protein and supported less virus production.
28280111
USP7 affects spindle pole
| 1
USP7 inhibits spindle pole. 1 / 1
| 1
eidos
Depletion of USP7 induced multiple spindle pole formation in mitosis , and , consequently , resulted in mitotic catastrophe .
33207738
USP7 affects sbmA
| 1
USP7 activates sbmA. 1 / 1
| 1
reach
Moreover, USP7 knockdown suppressed disease phenotypes in SBMA and spinocerebellar ataxia type 3 (SCA3) fly models, and monoallelic knockout of Usp7 ameliorated several motor deficiencies in transgenic SBMA mice.
33170804
USP7 affects replication fork
| 1
USP7 activates replication fork. 1 / 1
| 1
eidos
Depletion of USP7 leads to slowed replication fork progression and reduced origin firing [ 287 ] .
| PMC
USP7 affects pyrimidine
| 1
USP7 inhibits pyrimidine. 1 / 1
| 1
reach
Moreover, USP7 deficiency severely impairs the repair of cyclobutane pyrimidine dimers and, to a lesser extent, affects the repair of 6-4 photoproducts.
25118285
USP7 affects protein
| 1
USP7 inhibits protein. 1 / 1
| 1
eidos
As Usp7 is a deubiquitinase and prevents protein degradation , Uhrf1 protein abundance decreased in T cells after treatment with the Usp7 inhibitor ( Fig. 6 H ) .
31515281
USP7 activates protein deubiquitination. 1 / 1
| 1
eidos
USP7 directly interacted with PD-L1 and promoted its deubiquitination and stabilization As USP7 expression was positively correlated with PD-L1 expression in human GC tissues and abrogation of USP7 decreased the expression of PD-L1 in different GC cell lines , we next asked how USP7 regulates the PD-L1 expression .
33777676
USP7 affects polyubiquitin
| 1
USP7 inhibits polyubiquitin. 1 / 1
| 1
reach
This property of USP7 could be beneficial to suppress polyubiquitin signals.
30647135
USP7 inhibits polyinosinic-polycytidylic acid. 1 / 1
| 1
reach
Overexpression of USP7 suppressed Sendai virus and polyinosinic-polycytidylic acid and poly (deoxyadenylic-deoxythymidylic)-induced ISRE and IFN-beta activation, and enhanced virus replication.
29688809
USP7 increases the amount of peroxisomal biogenesis factor 11. 1 / 1
| 1
reach
The results showed that inhibition of USP7 increases expression of the AMPK beta (PRKAB1), caspase 7 (CASP7), and protein phosphatase 2 subunit B R3 isoform (PPP2R3A), while attenuating expression of C subunit of vacuolar ATPase (ATP6V0C), and peroxisomal biogenesis factor 11 beta (PEX11B).
33869052
USP7 affects pdaC
| 1
USP7 activates pdaC. 1 / 1
| 1
reach
In particular, pharmaceutical inhibition of USP7 by the small molecule P22077 attenuated PDAC cell growth and induced cell death in vitro and in vivo.
32468271
USP7 affects p38
| 1
USP7 inhibits p38. 1 / 1
| 1
reach
USP7 inhibition was shown to mediate MPhis reprogramming by activating the p38 MAPK pathway.
32802195
eidos
43 In conclusion , our study demonstrated that up-regulation of miR-15b could inhibit the expression of USP7 , which potentially suppress the osteoblast proliferation , differentiation and autophagy to aggravate osteoporosis through inhibition of KDM6B expression ( Figure 7 ) .
33434305
USP7 activates osteoblast differentiation. 1 / 1
| 1
eidos
36 Of note , our data revealed that inhibition of proteasome up-regulated expression of USP7 and KDM6B , while increased USP7 expression promoted osteoblast differentiation and autophagy , alleviating osteoporosis .
33434305
USP7 inhibits necrotic cell death. 1 / 1
| 1
reach
It was found that inhibition or downregulation of USP7 could not cause cell apoptosis and necrosis of NSCLC cells by the quantified reduction in cell number.
27590858
USP7 affects hCS
| 1
USP7 inhibits hCS. 1 / 1
| 1
sparser
Up- and down-regulation of TEF-1 levels by expression systems and antisense oligonucleotides demonstrated that TEF-1 inhibited the hCS promoter in a manner independent of the enhancer or a known TEF-1 DNA binding site.
7775450
reach
Inhibition of USP7 upregulates E-cadherin and downregulates Vimentin and N-cadherin, indicating USP7 promotes EMT in NSCLC.
28166483
USP7 affects dedifferentiation
| 1
USP7 activates dedifferentiation. 1 / 1
| 1
reach
It will be of significant interest and the focus of our future studies to define whether alterations in USP7 activity and thus the mono-ubiquitination status of PTEN underlie SMC dedifferentiation and vascular disease progression, which could lead to novel therapeutics that selectively target this system.
26940659
USP7 affects cytarabine
| 1
USP7 inhibits cytarabine. 1 / 1
| 1
reach
It is striking to note that USP7 inhibition potentiated the effects of cytarabine in cells that expressed high levels of USP7, leading to reduced colony formation, while it did not modify the sensitivity to cytarabine of cells that expressed low levels of USP7.
32447346
USP7 affects cyclobutane
| 1
USP7 inhibits cyclobutane. 1 / 1
| 1
reach
Moreover, USP7 deficiency severely impairs the repair of cyclobutane pyrimidine dimers and, to a lesser extent, affects the repair of 6-4 photoproducts.
25118285
USP7 inhibits cellular senescence. 1 / 1
| 1
reach
In contrast, knockdown of USP7 with two independent shRNAs caused senescence in both the Leiden and control fibroblasts.
20601937
USP7 activates breast cancer cell line. 1 / 1
| 1
eidos
This accumulation is in positive correlation with the literature showing that USP7 inhibition causes a G0-G1 arrest in breast cancer cell lines ( Xia at al ., 2019 ) .
32922122
USP7 affects bortezomib
| 1
USP7 inhibits bortezomib. 1 / 1
| 1
reach
A recent study demonstrated that inhibition of ubiquitin specific protease-7 (USP7), which normally stabilizes MDM2, triggers apoptosis in bortezomib resistant MM cells, confirming the idea of p53 downregulation as a DR mechanism in MM [XREF_BIBR].
24327604
eidos
Altogether , our findings highlighted that USP7 promoted the occurrence of LN by regulating the NF-kappaB p65 signaling pathway via stabilization of JMJD3 .
33895173
reach
USP7 has also been reported to modulate BER of oxidative lesions by modulating DNA accessibility and consequently the rate of repair of oxidative lesions through effects on chromatin remodelling [100].
23712866
USP7 affects angiogenesis
| 1
USP7 activates angiogenesis. 1 / 1
| 1
eidos
Collectively , these data indicated that FOXO6 promoted the proliferation and angiogenesis of EC by mediating USP7 expression via the JMJD3 / CLU pathway .
33768140
USP7 affects ZEB1
| 1
USP7 activates ZEB1. 1 / 1
| 1
reach
Conversely, knockdown of USP7 in SUM159-P2 cells reduced CHK1 stability (XREF_FIG and XREF_SUPPLEMENTARY) but not ZEB1 stability (XREF_SUPPLEMENTARY).
25086746
USP7 affects VIM
| 1
USP7 activates VIM. 1 / 1
| 1
reach
Inhibition of USP7 upregulates E-cadherin and downregulates Vimentin and N-cadherin, indicating USP7 promotes EMT in NSCLC.
28166483
USP7 affects VEGFA
| 1
USP7-K444R activates VEGFA. 1 / 1
| 1
reach
Western blot analysis showed that mouse Twist1, Vegf and Glut1 proteins were not induced by hypoxia in Hausp K444R fibroblasts (XREF_FIG).
27934968
USP7 activates Urinary Bladder Neoplasms. 1 / 1
| 1
reach
The immunohistochemical staining of both CCDC6 and USP7 proteins allowed to cluster the high grade (G3) UBC patients, on the basis of CCDC6 expression levels.
30786932
USP7 affects USP8
| 1
USP7 inhibits USP8. 1 / 1
| 1
reach
51) specific for USP7, HBX 90,397 inhibits USP8 (3) (Ref.
22088887
USP7 affects UBB
| 1
USP7 inhibits UBB. 1 / 1
| 1
reach
The inhibition of both USP7 and circ-DB increased the relative levels of ubiquitin-cyclin A2.
30546088
USP7 affects UBA52
| 1
USP7 activates UBA52. 1 / 1
| 1
reach
The results showed that CDDO-Me markedly inhibited the USP7 mediated cleavage of GST-UBA52 in an in vitro gel based assay.
27780924
USP7 affects TNF
| 1
USP7 activates TNF. 1 / 1
| 1
reach
Finally, the deubiquitinase USP7 promotes TNF induced transcriptional responses and nuclear p65 stability by deubiquitinating DNA bound p65 [XREF_BIBR].
24958609
USP7 affects TCN1
| 1
USP7 inhibits TCN1. 1 / 1
| 1
sparser
Up- and down-regulation of TEF-1 levels by expression systems and antisense oligonucleotides demonstrated that TEF-1 inhibited the hCS promoter in a manner independent of the enhancer or a known TEF-1 DNA binding site.
7775450
USP7 affects SVIL
| 1
USP7 inhibits SVIL. 1 / 1
| 1
reach
Knockdown of the p53 deubiquitinating enzyme USP7 and HAUSP also reverses the supervillin phenotype, blocking the increase in p53 levels seen after supervillin knockdown and accentuating the decrease in p53 levels triggered by supervillin overexpression.
23382381
USP7 affects STAT
| 1
USP7 inhibits STAT. 1 / 1
| 1
reach
Knockdown of USP7 expression consistently reduced the expression levels of signal transducer and activator of transcription (STAT)-1, STAT-2 and selected IFN inducible genes, including IFN induced protein with tetratricopeptide repeats 3, MX dynamin like GTPase 1 and 2 '-5'-oligoadenylate synthetase 1.
28656291
USP7 affects SREBF
| 1
USP7 activates SREBF. 1 / 1
| 1
reach
USP7 and ZNF638 axis selectively increased the cleavage of sterol regulatory element binding protein (SREBP1C) through AKT/mTORC1/S6K signaling, and formed USP7/ZNF638/SREBP1C nuclear complex to regulate lipogenesis associated enzymes, including acetyl-CoA carboxylase (ACACA), fatty acid synthase (FASN), and Stearoyl-CoA desaturase (SCD).
33040080
USP7 affects SPRTN
| 1
USP7 activates SPRTN. 1 / 1
| 1
reach
Finally, we show that the deubiquitylating enzyme USP7 antagonizes this negative control of SPRTN in the presence of DPCs.
33348378
USP7 affects SMAD3
| 1
USP7 activates SMAD3. 1 / 1
| 1
reach
In addition, cell-free and cell-based analyses further demonstrate that the deubiquitinase activity of USP7 mediates the removal of mono-ubiquitin from SMAD3 and facilitates the DNA-binding of SMAD3-SMAD4 dimer at SMAD3 locus, and thus enhance the autoregulation of SMAD3.
34580281
USP7 affects SLC9A3
| 1
USP7 decreases the amount of SLC9A3. 1 / 1
| 1
reach
Knockdown of USP7 or USP10 resulted in increased NHE3 ubiquitination and decreased NHE3 expression at the surface membrane and cellular level.
33095475
USP7 affects SLC7A11
| 1
USP7 activates SLC7A11. 1 / 1
| 1
reach
For example, in a non neuronal setting, induction of ferroptosis with the small molecule erastin is suppressed by the ubiquitin ligase NEDD4 [XREF_BIBR], whilst the DUBs OTUB1 and USP7 promote ferroptosis by stabilising the mediators SLC7A11 and p53, respectively [XREF_BIBR, XREF_BIBR].
33414510
USP7 affects SLC2A1
| 1
USP7-K444R activates SLC2A1. 1 / 1
| 1
reach
Western blot analysis showed that mouse Twist1, Vegf and Glut1 proteins were not induced by hypoxia in Hausp K444R fibroblasts (XREF_FIG).
27934968
USP7 affects SLC22A3
| 1
USP7 activates SLC22A3. 1 / 1
| 1
reach
Additionally, we also found that USP7 might induce cell epithelial-mesenchymal transition to enhance the cell invasive ability.
25519684
USP7 affects SLC22A18AS
| 1
USP7 inhibits SLC22A18AS. 1 / 1
| 1
sparser
Antisense TEF-1 delta mRNA-mediated inhibition of translation of TEF-1 delta protein, furthermore, resulted in inhibition of TEF-1 delta-mediated transformation of NIH3T3 cells as evidenced from the decrease in the number of transformed foci.
12210501
USP7 affects SIRT7
| 1
USP7 activates SIRT7. 1 / 1
| 1
reach
USP7 depletion by RNA interference increased both G6PC expression and SIRT7 enzymatic activity.
28655758
USP7 affects SHOC2
| 1
USP7 activates SHOC2. 1 / 1
| 1
reach
We identify that in the Shoc2 module USP7 functions as a molecular "switch" that controls the E3 ligase HUWE1 and the HUWE1-induced regulatory feedback loop.
34553755
USP7 affects SCIN
| 1
USP7 decreases the amount of SCIN. 1 / 1
| 1
reach
While USP7 silencing induced the expression of GHR, GDF8, SCIN and EHF (XREF_SUPPLEMENTARY), silencing MDM2 had no effect on the induction of these genes (XREF_SUPPLEMENTARY).
26971997
USP7 affects RNF220
| 1
USP7 inhibits RNF220. 1 / 1
| 1
trips
In colon cancer cells with stimulated Wnt signaling, knockdown of RNF220 or USP7 impairs Wnt signaling and expression of Wnt target genes, suggesting a potentially novel role of RNF220 in Wnt-related tumorigenesis.
25266658
USP7 affects RNF2
| 1
USP7 inhibits RNF2. 1 / 1
| 1
reach
USP7 inhibits the enzymatic activity of RNF2 through deubiquitination [XREF_BIBR].
25634095
USP7 affects RASA1
| 1
USP7 activates RASA1. 1 / 1
| 1
reach
The obtained results clearly highlight that deactivation of USP7 protein with its allosteric inhibitor p5091 decreased gap closure capability of MCF7 cells by 87.5%.
32922122
USP7 affects RAE1
| 1
USP7 activates RAE1. 1 / 1
| 1
reach
Among those identified were DNMT1, RAE1, Bub3 and Nup98, the stability and functions of which are potentially regulated by Hausp.
19946331
USP7 affects Protein Stability
| 1
USP7 activates Protein Stability. 1 / 1
| 1
eidos
A study reported that USP7 is critical for target gene transcription , whereby USP7 targeted NF-kappaB p65 for K48-linked deubiquitination , increased the protein stability of p65 , and ultimately led to increased transcription .
33511009
USP7 affects Protease
| 1
USP7 inhibits Protease. 1 / 1
| 1
reach
The relative ratio of Ci R to Ci FL was dramatically increased (from 1.00 to 2.15) in usp7 and hib double knockdown in wing discs compared to hib single knockdown in wing discs, indicating that Usp7 i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
26120032
USP7 affects Phosphatase
| 1
USP7 decreases the amount of Phosphatase. 1 / 1
| 1
reach
The results showed that inhibition of USP7 increases expression of the AMPK beta (PRKAB1), caspase 7 (CASP7), and protein phosphatase 2 subunit B R3 isoform (PPP2R3A), while attenuating expression of C subunit of vacuolar ATPase (ATP6V0C), and peroxisomal biogenesis factor 11 beta (PEX11B).
33869052
USP7 affects PTTG1
| 1
USP7 activates PTTG1. 1 / 1
| 1
reach
We tested if USP7 can rescue the APC/C substrates cyclin B1 and securin from degradation in mitotic extract.
33417828
USP7 affects PTHLH
| 1
USP7 activates PTHLH. 1 / 1
| 1
reach
USP7 knockdown or its inhibitor inhibited PTHrP and PTH1R signalling to exert its function.
33127578
USP7 affects PTH1R
| 1
USP7 activates PTH1R. 1 / 1
| 1
reach
USP7 knockdown or its inhibitor inhibited PTHrP and PTH1R signalling to exert its function.
33127578
USP7 affects PRRC2A
| 1
USP7 activates PRRC2A. 1 / 1
| 1
eidos
Therefore , the decreased USP7 amount caused an arrest in G1 phase and a decrease in G2 / M phase in MCF7 cells ( Figure 3 ) .
32922122
USP7 affects PRC1
| 1
USP7 inhibits PRC1. 1 / 1
| 1
reach
Examination of the PRC1 regulated INK4a locus found depletion of both USP7 and USP11 resulted in expression of p16 INK4a at the transcript and protein level, and decreased binding of PRC1 members at the INK4a locus as assessed by ChIP.
23845989
USP7 affects POT1
| 1
USP7 inhibits POT1. 1 / 1
| 1
reach
TSPYL5 Depletion Induces Specific Death of ALT Cells through USP7 Dependent Proteasomal Degradation of POT1.
31278054
USP7 affects POLQ
| 1
USP7 activates POLQ. 1 / 1
| 1
reach
Considering that aberrant USP7 expressions were frequently found in various tumors and elevated TLS is involved in resistance to chemotherapeutic agents, our findings that USP7 mediated stabilization of Poleta facilitates PCNA monoubiquitination mediated stress-tolerance pathways provide unique mechanistic insights for USP7 related tumorigenesis and may be useful for developing future therapeutic strategy.
25435364
USP7 affects PMAIP1
| 1
USP7 inhibits PMAIP1. 1 / 1
| 1
reach
For example, in esophageal cancer, USP7 inhibition upregulates Noxa, which in turn mediates p53 dependent apoptosis [XREF_BIBR, XREF_BIBR].
30897496
USP7 affects PLK1
| 1
USP7 activates PLK1. 1 / 1
| 1
reach
USP7 as a deubiquitinase sustained PLK1 protein stability via the C223 site, and inversely, USP7 inhibition by P5091 promoted the protein degradation of PLK1 through the ubiquitination-proteasome pathway.
31730000
USP7 affects PLA2G1B
| 1
USP7 activates PLA2G1B. 1 / 1
| 1
reach
In this study, we have expanded on the observations of Aleo and colleagues by demonstrating that NSC 632839 inhibits purified USP2- and USP7-mediated cleavage of Ub-PLA2 (Fig. 5A,B).
18424514
USP7 affects PDCD1
| 1
USP7 activates PDCD1. 1 / 1
| 1
eidos
These results demonstrate that abrogation of USP7 increased PD-L1 polyubiquitinaion , decreased the PD-1 / PD-L1 interaction and sensitized gastric cancer cells to T cell-mediated killing .
33777676
USP7 affects PCNA
| 1
USP7 activates PCNA. 1 / 1
| 1
reach
P22077 and USP7 knockdown could not decrease MCM2 and PCNA proteins, which were used as proliferative markers (Cates et al., 2015; Keshav and Narayanappa, 2015).
27590858
USP7 affects PARP1
| 1
USP7 inhibits PARP1. 1 / 1
| 1
reach
Furthermore, XREF_FIG showed that poly ADP-ribose polymerase (PARP) cleavage and cellular apoptosis were induced by USP7 inhibition.
33869052
USP7 affects PAFAH1B1
| 1
USP7 activates PAFAH1B1. 1 / 1
| 1
reach
Furthermore, pharmacological inhibition of USP7 markedly suppressed the growth of MDS cell lines in xenograft mouse models.
32130729
USP7 affects Osteoporosis
| 1
USP7 activates Osteoporosis. 1 / 1
| 1
eidos
36 Of note , our data revealed that inhibition of proteasome up-regulated expression of USP7 and KDM6B , while increased USP7 expression promoted osteoblast differentiation and autophagy , alleviating osteoporosis .
33434305
USP7 affects NUP98
| 1
USP7 activates NUP98. 1 / 1
| 1
reach
Among those identified were DNMT1, RAE1, Bub3 and Nup98, the stability and functions of which are potentially regulated by Hausp.
19946331
USP7 affects NMRAL1
| 1
USP7 activates NMRAL1. 1 / 1
| 1
reach
And USP7 partially rescued the growth rate of HSCARG -/- cells, while HSCARG did not rescue the growth rate of USP7 -/- cells.
24711370
reach
The study showed that treatment with P22077, an inhibitor of both USP7 and USP47, impairs NLRP3 inflammasome activation in macrophages, leading to the inhibition of IL-1β, IL-18, and caspase-1 cleavage and release, as well as pyroptotic cell death.
| PMC
USP7 affects NFKBIA
| 1
USP7 activates NFKBIA. 1 / 1
| 1
reach
Compared with control cells, knockout of USP7 in HCT116 cells stimulated the degradation of IkappaBalpha, while overexpression of USP7 in 293T cells completely abolished the degradation of IkappaBalpha.
24832601
USP7 affects Melanoma
| 1
USP7 activates Melanoma. 1 / 1
| 1
reach
Pharmacological inhibition of USP7 suppresses growth and metastasis of melanoma cells in vitro and in vivo.
34469054
USP7 affects MSTN
| 1
USP7 decreases the amount of MSTN. 1 / 1
| 1
reach
While USP7 silencing induced the expression of GHR, GDF8, SCIN and EHF (XREF_SUPPLEMENTARY), silencing MDM2 had no effect on the induction of these genes (XREF_SUPPLEMENTARY).
26971997
USP7 affects MMP1
| 1
USP7 activates MMP1. 1 / 1
| 1
reach
Results also indicated that MIA significantly upregulated USP7, NOX4, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was attenuated by the inhibition of USP7 with P22077 (XREF_FIG).
33584299
USP7 affects MDC1
| 1
USP7 activates MDC1. 1 / 1
| 1
reach
We demonstrate that USP7 mediated MDC1 stabilization promoted cervical cancer cell survival and conferred cellular resistance to genotoxic insults.
30179224
USP7 affects MCM7
| 1
USP7 activates MCM7. 1 / 1
| 1
reach
P22077 and USP7 knockdown could not decrease MCM2 and PCNA proteins, which were used as proliferative markers (Cates et al., 2015; Keshav and Narayanappa, 2015).
27590858
USP7 affects MCF-7 Cells
| 1
USP7 activates MCF-7 Cells. 1 / 1
| 1
eidos
Our results show that suppression of USP7 activity via p5091 and siUSP7 caused a decrease in cell proliferation for both MCF7 and T47D cell lines regardless of their TP53 mutation status .
32922122
USP7 affects Leu-Asn
| 1
USP7 activates Leu-Asn. 1 / 1
| 1
reach
Altogether, our findings highlighted that USP7 promoted the occurrence of LN by regulating the NF-kappaB p65 signaling pathway via stabilization of JMJD3.
33895173
USP7 affects Hepatoblastoma
| 1
USP7 activates Hepatoblastoma. 1 / 1
| 1
eidos
USP7 promotes hepatoblastoma progression through activation PI3K / AKT signaling pathway .
33780361
USP7 affects HMBS
| 1
USP7 inhibits HMBS. 1 / 1
| 1
reach
We also used two inhibitors targeting non proteasomal UPS components : PYR-41, an inhibitor of ubiquitin E1 ligase and several DUBs, and P5091, a specific USP7 and USP47 inhibitor 32.
30858500
USP7 affects GSN
| 1
USP7 activates GSN. 1 / 1
| 1
reach
USP7 inhibition inhibits proliferation and induces megakaryocytic differentiation in MDS cells by upregulating gelsolin.
32130729
USP7 affects GMPS
| 1
USP7 decreases the amount of GMPS. 1 / 1
| 1
reach
Down-regulation of USP7 reduced the level of GMPS at the FR, increased the level of monoubiquitylated H2B in this region of the origin and decreased the ability of EBNA1, but not an EBNA1 USP7 binding mutant, to activate transcription from the FR.
19834552
USP7 affects GMNN
| 1
USP7 decreases the amount of GMNN. 1 / 1
| 1
reach
Conversely, depletion of DUB3 or USP7 reduces Geminin levels, and DUB3 knockdown increases re-replication events, analogous to the effect of Geminin depletion.
28288134
USP7 affects GEF
| 1
USP7 activates GEF. 1 / 1
| 1
reach
Taken together, these results suggested that ECT2 counteracts the polyubiquitination of USP7 thus promotes USP7 stabilization in a GEF activity independent manner.
32929379
USP7 affects GATA3
| 1
USP7 activates GATA3. 1 / 1
| 1
reach
In a search for DUBs that contribute to GATA3 stabilization in FOXP3-expressing cells, both USP7 and USP21 were shown to upregulate GATA3-mediated activity using a reporter assay 131 .
28959952
USP7 affects GATA1
| 1
USP7 decreases the amount of GATA1. 1 / 1
| 1
reach
Mechanistically, USP7 deficiency led to decreased GATA1 protein level that can be reversed by proteasome inhibitors.
30872372
USP7 affects G1 phase
| 1
USP7 activates G1 phase. 1 / 1
| 1
reach
USP7 silencing in HL-60 cells (Supplementary Fig. 1A) significantly reduced cell proliferation (Fig. 1a) by increasing apoptotic cell death (Fig. 1b) and the proportion of cells in the G1 phase (Fig. 1c).
32447346
USP7 affects Forkhead
| 1
USP7 activates Forkhead. 1 / 1
| 1
reach
USP7 has been shown to inactivate several tumor suppressors including P53, FOXO4 (Forkhead box O4) and PTEN (phosphatase and tensin homolog deleted on chromosome ten) through different mechanisms, which lead to tumorigenesis [XREF_BIBR - XREF_BIBR].
25481052
USP7 affects FUS
| 1
USP7 inhibits FUS. 1 / 1
| 1
reach
USP7 suppresses oxidative stress induced mutagenesis by decreasing the level of mono-ubiquitinated PCNA [61], suggesting that USP7 prevents the excessive activation of mutagenic TLS polymerases.
28666590
USP7 affects FOXO1
| 1
USP7 inhibits FOXO1. 1 / 1
| 1
reach
For example, the deubiquitylase MATH-33 recently has been reported to stabilize and activate DAF-16 by antagonizing polyubiquitylation, while its mammalian counterpart USP7 and HAUSP inhibits FOXO1 and FOXO4 by decreasing their nuclear localization and transcriptional activity, respectively, by removing monoubiquitin moieties [XREF_BIBR - XREF_BIBR].
28562327
USP7 affects FBXL21P
| 1
USP7 inhibits FBXL21P. 1 / 1
| 1
reach
However, it is still possible that USP7 may antagonize the action of FBXL21 by cleaving the ubiquitin chain (s) formed by FBXL21.
27123980
USP7 affects FASLG
| 1
USP7 activates FASLG. 1 / 1
| 1
reach
USP7 promotes APL, aggressive prostate cancer, and NSCLC metastasis.
28166483
USP7 affects Epsilon
| 1
USP7 inhibits Epsilon. 1 / 1
| 1
reach
On the other hand, the epsilon-NH signal of Trp 232 was perturbed by binding of the TRAF-DUB-containing HAUSP 62-560, but not by binding of the TRAF containing HAUSP 62-205 (XREF_FIG, blue).
22056774
USP7 affects ERK
| 1
USP7 activates ERK. 1 / 1
| 1
reach
Moreover, USP7 siRNA blocked the activation of Akt/ERK signaling pathway.
34812471
USP7 affects EHF
| 1
USP7 decreases the amount of EHF. 1 / 1
| 1
reach
While USP7 silencing induced the expression of GHR, GDF8, SCIN and EHF (XREF_SUPPLEMENTARY), silencing MDM2 had no effect on the induction of these genes (XREF_SUPPLEMENTARY).
26971997
USP7 affects DSPP
| 1
USP7 decreases the amount of DSPP. 1 / 1
| 1
reach
Indeed, inactivation of Usp7 increased the ratio of Ci R / Ci FL and caused reduction of dpp expression.
26120032
USP7 activates DNA damage checkpoint. 1 / 1
| 1
reach
USP7 is one of the best studied deubiquitinases and also contributes to the DNA damage response through regulating the stability of MDM2 or p53 19.
25865756
USP7 affects DLL1
| 1
USP7 inhibits DLL1. 1 / 1
| 1
sparser
Antisense TEF-1 delta mRNA-mediated inhibition of translation of TEF-1 delta protein, furthermore, resulted in inhibition of TEF-1 delta-mediated transformation of NIH3T3 cells as evidenced from the decrease in the number of transformed foci.
12210501
USP7 affects CXCL8
| 1
USP7 inhibits CXCL8. 1 / 1
| 1
reach
33 We also assessed the effect of USP7 on TNFalpha induced IL-8 activation, and the result showed that USP7 strongly suppressed the activation of IL-8 (XREF_FIG).
24832601
USP7 affects CRYL1
| 1
USP7 activates CRYL1. 1 / 1
| 1
reach
To ask whether USP7 specifically inhibits CRY degradation promoted by FBXL3, we examined USP7 mediated stabilization of CRY in Fbxl3-knockdown cells (XREF_SUPPLEMENTARY).
27123980
USP7 affects CHFR
| 1
USP7 bound to CHFR activates CHFR. 1 / 1
| 1
reach
Taken together, these results clearly indicate that USP7 binds to Chfr and increases the stability of Chfr in vivo.
17442268
USP7 affects CDKN1C
| 1
USP7 decreases the amount of CDKN1C. 1 / 1
| 1
reach
Mechanistically, USP7 inhibited p57 KIP2 expression by modulating TBX3, directly binding to TBX3, and decreasing its ubiquitination and degradation.
32966862
USP7 affects CDH2
| 1
USP7 activates CDH2. 1 / 1
| 1
reach
Inhibition of USP7 upregulates E-cadherin and downregulates Vimentin and N-cadherin, indicating USP7 promotes EMT in NSCLC.
28166483
USP7 affects CDH1
| 1
USP7 inhibits CDH1. 1 / 1
| 1
reach
Inhibition of USP7 upregulates E-cadherin and downregulates Vimentin and N-cadherin, indicating USP7 promotes EMT in NSCLC.
28166483
USP7 affects CD
| 1
USP7 activates CD. 1 / 1
| 1
reach
A C-terminal peptide of USP7 further activates the CD activity by binding to an adjacent activation cleft to stabilize the active conformation of USP7 (7) .
30914461
USP7 affects CCNB1
| 1
USP7 activates CCNB1. 1 / 1
| 1
reach
We tested if USP7 can rescue the APC/C substrates cyclin B1 and securin from degradation in mitotic extract.
33417828
USP7 affects CCK
| 1
USP7 inhibits CCK. 1 / 1
| 1
reach
In addition, we found that USP7 depleted cells transfected with exogenous ARMC5 fully prevented the cell proliferation using the CCK-8 assay.
33544460
USP7 affects CCD
| 1
USP7 activates CCD. 1 / 1
| 1
reach
Hausp haploinsufficiency causes CCD.
32385263
USP7 affects CASP7
| 1
USP7 decreases the amount of CASP7. 1 / 1
| 1
reach
The results showed that inhibition of USP7 increases expression of the AMPK beta (PRKAB1), caspase 7 (CASP7), and protein phosphatase 2 subunit B R3 isoform (PPP2R3A), while attenuating expression of C subunit of vacuolar ATPase (ATP6V0C), and peroxisomal biogenesis factor 11 beta (PEX11B).
33869052
USP7 affects CASC3
| 1
USP7 inhibits CASC3. 1 / 1
| 1
reach
Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing IotakappaBetaalpha and blocking the NF-kappaB pathway.
30024656
USP7 affects Bre1
| 1
USP7 decreases the amount of Bre1. 1 / 1
| 1
reach
However, we did not observe any changes in the cellular levels of Bre1 following USP7 knockdown suggesting that, most probably, Mdm2 is ubiquitylating histones and that the observed defects in DNA repair and chromatin accessibility following USP7 knockdown observed in our experiments is due to the reduction in the levels of Mdm2 through self ubiquitylation (XREF_FIG B).
21138959
USP7 affects BRCA1
| 1
USP7 decreases the amount of BRCA1. 1 / 1
| 1
reach
We showed that USP7 disruption impairs H2A and ultraviolet radiation (UVR)-induced gammaH2AX monoubiquitination, and decreases the levels of pBmi1, Bmi1, RNF168 and BRCA1.
25894431
USP7 affects BIRC3
| 1
USP7 activates BIRC3. 1 / 1
| 1
reach
Furthermore, DUBs are known to regulate stability of only 4 of these proteins, including the ubiquitin ligases MARCH7 and BIRC3, which are targeted by USP7 or USP9 and USP19, respectively.
33417828
USP7 affects BCR
| 1
USP7 activates BCR. 1 / 1
| 1
reach
In line with this finding, genetic or chemical inhibition of USP7 leads to BCR-ABL protein degradation, suppresses BCR and ABL signaling, and induces CML cell apoptosis.
33963175
USP7 affects BCL2L1
| 1
USP7 inhibits BCL2L1. 1 / 1
| 1
reach
As p53 can antagonize the anti-apoptotic effects of Bcl-2 and Bcl-xL [XREF_BIBR], USP7 may inhibit the Bcl-2 and Bcl-xL anti-apoptotic effect by negatively regulating p53.
25519684
USP7 affects BCL2
| 1
USP7 inhibits BCL2. 1 / 1
| 1
reach
As p53 can antagonize the anti-apoptotic effects of Bcl-2 and Bcl-xL [XREF_BIBR], USP7 may inhibit the Bcl-2 and Bcl-xL anti-apoptotic effect by negatively regulating p53.
25519684
USP7 affects BACH1
| 1
USP7 activates BACH1. 1 / 1
| 1
reach
Chromatin IP (ChIP)-quantitative polymerase chain reaction (qPCR) assays confirmed that Bach1 occupied the Usp7 promoter (XREF_FIG), indicating that Usp7 is a direct target of Bach1, and when Usp7 activity was down-regulated via transfection with small interfering RNAs (siRNAs) and/or treatment with the Usp7 inhibitor P5091, Nanog ubiquitination increased, pluripotency protein levels declined in WT hESCs, and the increase in pluripotency protein levels associated with Bach1 overexpression was abolished (XREF_FIG and fig.
30891497
USP7 affects Aging
| 1
USP7 inhibits Aging. 1 / 1
| 1
reach
Consistently, cell senescence could be induced by HAUSP and USP7 knockdown.
26697514
USP7 activates Adenomatous Polyposis Coli. 1 / 1
| 1
eidos
USP7 also activates Wnt signaling in adenomatous polyposis coli gene ( APC ) - mutated colorectal cancer through beta-catenin deubiquitination ( Novellasdemunt et al. 2017 ) .
33165832
USP7 affects Actin
| 1
USP7 activates Actin. 1 / 1
| 1
reach
Thus, USP7 functions as a rheostat for MAGEL2-TRIM27 function that enable fine tuning of actin nucleation.
28626083
USP7 affects ATXN3
| 1
USP7 activates ATXN3. 1 / 1
| 1
reach
Moreover, USP7 knockdown suppressed disease phenotypes in SBMA and spinocerebellar ataxia type 3 (SCA3) fly models, and monoallelic knockout of Usp7 ameliorated several motor deficiencies in transgenic SBMA mice.
33170804
USP7 affects ASXL1
| 1
USP7 decreases the amount of ASXL1. 1 / 1
| 1
reach
Knockdown of USP7 reduced ASXL1 expression in HL60 cells.
29423272
USP7 affects AR
| 1
USP7 activates AR. 1 / 1
| 1
reach
In prostate cancer, HAUSP deubiquitinates and rescues androgen receptor (AR) upon androgen stimulation and subsequently upregulates AR responsive gene expression by direct association with AR on chromatin.
29967688
USP7 affects ADP-ribose
| 1
USP7 inhibits ADP-ribose. 1 / 1
| 1
reach
Furthermore, XREF_FIG showed that poly ADP-ribose polymerase (PARP) cleavage and cellular apoptosis were induced by USP7 inhibition.
33869052
USP7 affects ABL_family
| 1
USP7 activates ABL_family. 1 / 1
| 1
reach
In line with this finding, genetic or chemical inhibition of USP7 leads to BCR-ABL protein degradation, suppresses BCR and ABL signaling, and induces CML cell apoptosis.
33963175
reach
Indeed, HAUSP knockdown suppressed BrdU incorporation in a manner analogous to N-Myc knockdown in both SK-N-DZ and IMR-32 cells (XREF_SUPPLEMENTARY).
27618649
UHRF1 affects USP7
| 1
UHRF1 inhibits USP7. 1 / 1
| 1
eidos
Thus , our data revealed that loss of USP7 variably reduced DNMT1 and UHRF1 protein stability , presumably due to its deubiquitinase activity toward DNMT1 and UHRF1 as reported previously38-41 .
32884836
TRIM28 affects USP7
| 1
TRIM28 inhibits USP7. 1 / 1
| 1
reach
Proteomic and immunoprecipitation analyses further reveal that the SIM3 motif is required for the EBNA1 mediated inhibitory effects on SUMO2 modified STUB1, SUMO2 mediated degradation of USP7, and SUMO1 modified KAP1.
32176739
TRAF affects USP7
| 1
TRAF inhibits USP7. 1 / 1
| 1
reach
On the other hand, the epsilon-NH signal of Trp 232 was perturbed by binding of the TRAF-DUB-containing HAUSP 62-560, but not by binding of the TRAF containing HAUSP 62-205 (XREF_FIG, blue).
22056774
TGM1 affects USP7
| 1
TGM1 increases the amount of USP7. 1 / 1
| 1
reach
Li et al.88 found that FTO promotes the proliferation of NSCLC by increasing the expression of USP7.
| PMC
TBPL1 affects USP7
| 1
TBPL1 activates USP7. 1 / 1
| 1
reach
Whether TRF2 modulates HAUSP or beta-TrCP function to indirectly affect REST stability is under investigation.
21258371
Soot affects USP7
1 |
Soot increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
26551751
SUMO3 affects USP7
| 1
SUMO3 inhibits USP7. 1 / 1
| 1
reach
Proteomic and immunoprecipitation analyses further reveal that the SIM3 motif is required for the EBNA1 mediated inhibitory effects on SUMO2 modified STUB1, SUMO2 mediated degradation of USP7, and SUMO1 modified KAP1.
32176739
STT3A affects USP7
| 1
STT3A activates USP7. 1 / 1
| 1
reach
Because the B5 shHAUSP targets the 3 '-end non coding region of endogenous HAUSP mRNA while the Wt-HAUSP and Mt-HAUSP constructs do not contain the 3 '-end non coding sequence, mRNA from Wt-HAUSP or Mt-HAUSP is not targeted by B5 shHAUSP.
21258371
STK11 affects USP7
| 1
STK11 inhibits USP7. 1 / 1
| 1
reach
In SAMe-D cells, the partial reduction of LKB1 levels induces nuclear accumulation of HAUSP compartment after UVC treatment.
20815019
STAT3 affects USP7
1 |
STAT3 decreases the amount of USP7. 1 / 1
1 |
trrust
No evidence text available
22750444
SPRR2B affects USP7
| 1
SPRR2B inhibits USP7. 1 / 1
| 1
reach
Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7 and MDM2 binding and p53 degradation, leading to CF cell cycle arrest.
29581288
SOCS1 affects USP7
| 1
SOCS1 inhibits USP7. 1 / 1
| 1
reach
Given the positive results from SOCS1 and SOCS3 inhibitors in reducing viral loads, such as pJAK2 1001–1013, miRNA‐19a, ubiquitin‐specific protease 7 (USP7) and zoledronic acid (ZA), it is important to consider the potential of SOCS inhibitors in the context of SARS‐CoV‐2 infection.
34546610
SCGN affects USP7
| 1
SCGN inhibits USP7. 1 / 1
| 1
reach
Previously, we have uncovered XREF_BIBR that Scgn can also inhibit the enzymatic activity of USP7 and USP9X ubiquitin carboxyl-terminal hydrolases and, consequently, increase the stability of their substrates.
29910119
Radiation, Ionizing decreases the amount of USP7. 1 / 1
| 1
reach
These seemingly-inconsistent results could be explained by the findings that ATF3 mediated Tip60 stabilization was USP7 dependent (XREF_FIG) and that USP7 expression was decreased by IR (XREF_SUPPLEMENTARY) as previously reported 32.
25865756
RCA affects USP7
| 1
RCA inhibits USP7. 1 / 1
| 1
sparser
UCHL1, UCHL3, USP2 and USP8 were found to be inhibited by AM146, RA-9, and RA-14, which did not inhibit Ataxin-3, A20, BAP1, Otubain 1 or USP7 ( xref ).
28279784
RBFOX2 affects USP7
| 1
RBFOX2 activates USP7. 1 / 1
| 1
reach
Additionally, RTA targets the USP7 to stabilize the HECT-type E3, RAUL.
22375140
RASSF affects USP7
| 1
RASSF-1A inhibits USP7 bound to MDM2 and DAXX. 1 / 1
| 1
trips
The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex.
18566590
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma increases the amount of USP7. 1 / 1
| 1
reach
Previous reports have documented the transcriptional regulation of USP7, for instance in T-cell acute lymphoblastic leukemia (T-ALL) in which the transcription factor NOTCH1 induces USP7 gene expression, and where USP7 controls the stability of NOTCH1 and the JMJD3 histone demethylase through a positive regulatory loop [37, 38].
32447346
Precursor Cell Lymphoblastic Leukemia-Lymphoma increases the amount of USP7. 1 / 1
| 1
reach
Previous reports have documented the transcriptional regulation of USP7, for instance in T-cell acute lymphoblastic leukemia (T-ALL) in which the transcription factor NOTCH1 induces USP7 gene expression, and where USP7 controls the stability of NOTCH1 and the JMJD3 histone demethylase through a positive regulatory loop [37, 38].
32447346
Plant Extracts affects USP7
1 |
Plant Extracts increases the amount of USP7. 1 / 1
1 |
ctd
No evidence text available
23557933
Phthalic Acids affects USP7
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Phthalic Acids increases the amount of USP7. 1 / 1
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ctd
No evidence text available
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Papillomavirus Infections activates USP7. 1 / 1
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Therefore , we tested whether HPV promotes USP7 expression and if HPV-induced USP7 can regulate TXNIP expression through up-regulation of UHRF1 .
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PRH2 affects USP7
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PRH2 activates USP7. 1 / 1
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Treatment of cells with probe 1 led to labeling of USP15 and USP7, but not by HA-Ub-PA (XREF_SUPPLEMENTARY).
30240200
POU1F1 affects USP7
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POU1F1 activates USP7. 1 / 1
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We identified USP7 as a PiT1 binding partner and demonstrated that Pit1 deletion inhibited USP7 and IRS1 dissociation upon insulin stimulation.
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PKC affects USP7
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PKC activates USP7. 1 / 1
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B-MHC gene expression is induced by complex effects of transcription factors, including SRF and MEF2 under control of HDACs (histone deacetylases), and PKC-activated TEF1 [ xref ].
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PDGF affects USP7
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PDGF increases the amount of USP7. 1 / 1
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Our results indicated that PDGF up-regulated USP7 protein expression and stimulated PASMCs proliferation; this was accompanied with the increase of MDM2, forkhead box O4 (FoxO4) reduction and elevation of CyclinD1.
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sparser
However, mutation of all three TEF-1 sites prevented detectable activation by T antigen.
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USP7 is modified
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USP7 is produced. 1 / 1
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ELISA and Western blotting results indicated that USP7 overexpression significantly increased IL-1beta and IL-18 levels as well as the expression of USP7, NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, MMP1, and MMP13, which was decreased by USP7 KD or apocynin (XREF_FIG).
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NFE2L1 affects USP7
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NFE2L1 increases the amount of USP7. 1 / 1
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Expression of wild type USP7, but not its catalytically defective mutant, resulted in decreased ubiquitination of TCF11 and Nrf1a, leading to their increased stability, and increased transactivation of reporter gene expression by TCF11 and Nrf1a.
33933455
NCL affects USP7
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NCL inhibits USP7. 1 / 1
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The ubiquitination level of nucleolin following knockdown of endogenous HAUSP was increased, as expected (XREF_FIG, lane 2).
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MLN7243 affects USP7
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MLN7243 desumoylates USP7. 1 / 1
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ctd
No evidence text available
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MBD4 affects USP7
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MBD4 activates USP7. 1 / 1
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XREF_FIG, the MBD4 induced USP7 relocation and their co-localization at chromocenters also leads to a degree of heterochromatin reorganization that was not evident in the single transfections.
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Lys-Gly affects USP7
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Lys-Gly activates USP7. 1 / 1
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An acetylation mimic mutant (DNMT1 4KQ) or acetylation of four Lysine residues on the KG linker of DNMT1 led to a decrease in its binding affinity to USP7 and a decrease in its protein stability.
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KDM6B affects USP7
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KDM6B activates USP7. 1 / 1
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Meanwhile, silencing of JMJD3 inhibited the promotive effect of USP7 on the proliferation of mesangial cells and mesangial matrix.
33895173
KAT5 affects USP7
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KAT5 inhibits USP7. 1 / 1
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It has been recently reported that TIP60 impairs this protective association of USP7 with DNMT1 by acetylation [XREF_BIBR].
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Interferon affects USP7
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Interferon inhibits USP7. 1 / 1
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Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein.
22056774
IRS2 affects USP7
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IRS2 activates USP7. 1 / 1
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The result indicated that insulin stimulation decreased the affinity of IRS-2 for the MATH domain, and this decrease was prevented by the treatment of cells with LY294002, suggesting that phosphorylat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
22634009
IL2 affects USP7
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IL2 activates USP7. 1 / 1
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Our ChIP studies confirmed decreased binding of Foxp3 to the IL-2 promoter of Usp7 targeted Tregs, along with their production of IL-2 and other normally repressed cytokines.
27769803
IGF1 affects USP7
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IGF1 activates USP7. 1 / 1
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We also demonstrate that insulin or IGF-I treatment stimulates USP7 dissociation from IRSs via activation of PI3K pathway, leading to degradation of IRSs.
22634009
HBX affects USP7
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HBX inhibits USP7. 1 / 1
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In another study , the assay showed that HBX 19818 inhibited USP7 , and the ubiquitination of MDM2 , a substrate of USP7 was increased by HBX 19818 treatment in a dose-dependent manner [ 60 ] .
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GMNN affects USP7
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Modified GMNN increases the amount of USP7. 1 / 1
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Overexpression of either DUB3 or USP7 increases Geminin levels through reduced ubiquitination.
28288134
GLI1 affects USP7
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GLI1 increases the amount of USP7. 1 / 1
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It should be interesting to determine whether Gli activity contributes to hausp overexpression induced tumors.
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GEF affects USP7
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GEF leads to the deubiquitination of USP7. 1 / 1
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Furthermore, we revealed that ECT2 and GEF mt promotes USP7 deubiquitination as efficiently as ECT2/wt does.
32929379
FOXO4 affects USP7
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FOXO4 activates USP7. 1 / 1
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Whether these compounds inhibit cancer cell proliferation independent of p53, for example through other USP7 targets such as FOXO4, PTEN, Claspin [XREF_BIBR], remains to be determined.
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Epsilon affects USP7
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Epsilon inhibits USP7. 1 / 1
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On the other hand, the epsilon-NH signal of Trp 232 was perturbed by binding of the TRAF-DUB-containing HAUSP 62-560, but not by binding of the TRAF containing HAUSP 62-205 (XREF_FIG, blue).
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ERK affects USP7
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ERK activates USP7. 1 / 1
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Here we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7.
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CYLD affects USP7
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CYLD deubiquitinates USP7. 1 / 1
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CYLD : cylindromatosis; DUB : deubiquitylating enzyme; EBNA : Epstein-Barr nuclear antigen; FOXO : forkhead box O; HAUSP : herpesvirus associated ubiquitin specific peptidase; JAMM : Jab1 and MPN domain associated metalloisopeptidase; MJD : Machado-Joseph disease; OUT : ovarian tumor; PD : Parkinson 's disease; RIP : receptor interacting protein; TNF : tumor necrosis factor; TRAF : tumor necrosis factor receptor associated factor; UBP : ubiquitin processing peptidase; USP : ubiquitin specific peptidase; UCH : ubiquitin C-terminal hydrolase; VHL : von Hippel-Lindau.
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CRYL1 affects USP7
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CRYL1 activates USP7. 1 / 1
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Cry -/- cells were used as a control to subtract the non specific ubiquitin signal and enable quantitative comparison of control and Hausp depleted cells.)
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CLU affects USP7
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CLU activates USP7. 1 / 1
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Previous research showed that CLU expression was positively related with JMJD3, XREF_BIBR so we assumed that CLU, as a downstream target gene of FOXO6, mediated the USP7 and JMJD3 pathway in the context of EC progression.
33768140
CK2 affects USP7
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CK2 activates USP7. 1 / 1
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reach
Since these cells expressed mostly USP7 isoform 1, the one with serine 18, these data suggest that CK2 promotes USP7 stabilization in CLL context, through phosphorylation.
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CHN1 affects USP7
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CHN1 inhibits USP7. 1 / 1
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It was added into cells to obtain a final concentration of 0, 5, 10, 20, and 40 muM at 24 h after cell seeding.Short hairpin RNA (shRNA) sequences targeting USP7 (si-USP7 :5 '-CTCAGAACCCTGTGATCAA-3 ')[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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CDKN1A affects USP7
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CDKN1A decreases the amount of USP7. 1 / 1
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reach
Furthermore, p21 and bax protein expression was significantly lower in tumours with either mutant p53 or reduced HAUSP expression than in tumours with both wild-type p53 and positive HAUSP expression (p = 0.0440 and p = 0.0046, respectively).
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CCDC6 affects USP7
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CCDC6 inhibits USP7. 1 / 1
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CCDC6 encodes for a pro apoptotic protein, often inactivated in thyroid and lung cancer upon fusion with various oncogenes [XREF_BIBR - XREF_BIBR]; CCDC6 is also impaired by somatic mutations, detected at low frequency in several tumors including bladder cancer (http://www.cbioportal.org/), as well as by its increased downregulation due to altered tuning of its modifying enzymes, the Fbxw7 E3 ubiquitin ligase and the USP7 deubiquitinase [XREF_BIBR].
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BRCC3 affects USP7
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BRCC3 deubiquitinates USP7. 1 / 1
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To identify the DUB associated with NALP7, we over-expressed plasmids expressing several candidate DUBs including BRCC3, which deubiquitinates NALP3, COPS5, STAMBPL1, USP7 and the endosome associated DUBs, STAMBP and USP8.
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BAX affects USP7
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Modified BAX increases the amount of USP7. 1 / 1
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reach
Furthermore, p21 and bax protein expression was significantly lower in tumours with either mutant p53 or reduced HAUSP expression than in tumours with both wild-type p53 and positive HAUSP expression (p = 0.0440 and p = 0.0046, respectively).
16450335
BACH1 affects USP7
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BACH1 increases the amount of USP7. 1 / 1
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reach
In this study, we demonstrated that Bach1 directly targets and increases the expression of Usp7 in hESCs and that Bach1 interacts with Nanog, Sox2, and Oct4 and recruits Usp7, which facilitates pluripotency protein deubiquitination and maintains hESC stemness.
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Antirheumatic Agents increases the amount of USP7. 1 / 1
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ctd
No evidence text available
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Antigens, Polyomavirus Transforming increases the amount of USP7. 1 / 1
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ctd
No evidence text available
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AVP affects USP7
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AVP decreases the amount of USP7. 1 / 1
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Verteporfin (VP) effectively inhibited the proliferation of colon cancer cells and organoids and could even modulate serine metabolism by inhibiting USP7 expression.
34055773
ATP affects USP7
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ATP activates USP7. 1 / 1
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375 distinct proteins were identified where ATP dependent RNA helicase DDX3, HNRPU, Matrin-3, Importin-7 and Bax were among the 25 most upregulated proteins and Hausp and UBP7, UBE2N and ERp29 among the 17 most downregulated.
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ADM affects USP7
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ADM inhibits USP7. 1 / 1
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UCHL1, UCHL3, USP2 and USP8 were found to be inhibited by AM146, RA-9, and RA-14, which did not inhibit Ataxin-3, A20, BAP1, Otubain 1 or USP7 ( xref ).
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ctd
No evidence text available
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4-hydroxyphenyl retinamide increases the amount of USP7. 1 / 1
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ctd
No evidence text available
28973697
3-isobutyl-1-methyl-7H-xanthine increases the amount of USP7. 1 / 1
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ctd
No evidence text available
28628672
3,4-methylenedioxymethamphetamine decreases the amount of USP7. 1 / 1
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ctd
No evidence text available
26251327
2-methyl-5-propan-2-ylcyclohexa-2,5-diene-1,4-dione activates USP7. 1 / 1
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However, TQ induced HAUSP and UHRF1 deregulation needs further investigation to decipher the molecular events involved, namely the HAUSP down-regulation, which triggers UHRF1 down-regulation followed by apoptosis.
29983883
2,3,7,8-tetrachlorodibenzodioxine increases the amount of USP7. 1 / 1
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ctd
No evidence text available
17942748
17beta-estradiol affects USP7
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17beta-estradiol increases the amount of USP7. 1 / 1
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ctd
No evidence text available
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17alpha-ethynylestradiol increases the amount of USP7. 1 / 1
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ctd
No evidence text available
17942748
eidos
WP1130 and BAY-11-7082 inhibit not only USP7 , but also a diverse set of additional DUBs ( Ritorto et al ., 2014 ) .
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4,4'-sulfonyldiphenol increases the amount of USP7. 1 / 1
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ctd
No evidence text available
28628672
3,3',5,5'-tetrabromobisphenol A decreases the amount of USP7. 1 / 1
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ctd
No evidence text available
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