USP13 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 13
HGNC Gene Symbol
USP13
Identifiers
hgnc:12611 NCBIGene:8975 uniprot:Q92995
Orthologs
mgi:1919857 rgd:1306044
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP13
Number of Papers
81 retrieved on 2022-05-22

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
KRTCAP2 keratinocyte associated protein 2 0.255
ZNF444 zinc finger protein 444 0.239 0.10 0.44 1.73e-01
OR7G2 olfactory receptor family 7 subfamily G member 2 -0.238
PCDHA2 protocadherin alpha 2 0.233
SH2D5 SH2 domain containing 5 0.23
KCNJ1 potassium inwardly rectifying channel subfamily J member 1 0.226
TRAK2 trafficking kinesin protein 2 0.223 Reactome (1) 0.19 0.97 1.86e-02

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP13using 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

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP13 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
CST4 cystatin S 6.68e-01 1.34e-06 2.97e-02
CST1 cystatin SN 6.12e-01 3.26e-06 3.60e-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 USP13 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 lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP13 deubiquitinates UIMC1. 10 / 16
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We demonstrated that polyubiquitination of RAP80 blocks its interaction with polyubiquitin chain and deubiquitination of RAP80 by USP13 facilitate the interaction between RAP80 and polyubiquitin chain.

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Together with results showing USP13 is important for DDR and RAP80 localization at the sites of DNA damage, we hypothesized that RAP80 ubiquitination is inhibitory of its function, and deubiquitination of RAP80 by USP13 following DNA damage promotes RAP80 function in the DDR pathway.

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In addition, USP13 specific inhibitor, Spautin-1, significantly enhanced RAP80 ubiquitination in control but not USP13 deficient cells (XREF_FIG).

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USP13 interacts with and deubiquitinates RAP80.

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USP13, in turn, deubiquitinates RAP80 and promotes RAP80 recruitment and proper DDR.

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We found that following DNA damage, a deubiquitinase, USP13, deubiquitinates RAP80 and promotes binding between RAP80 and K63 linked polyubiquitin chains, which is important for the recruitment of the RAP80 and BRCA1 complex to DSBs to facilitate DDR.

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USP13 deubiquitinates receptor associated protein 80 (RAP80) and promotes DNA damage response.

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USP13, in turn, deubiquitinates RAP80 and promotes RAP80 recruitment and proper DDR.

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Our results suggest that USP13 deubiquitinates RAP80 following DNA damage, which in turn facilitates RAP80 recruitment to DSBs.

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Consistent with this, we found that RAP80 ubiquitination decreases following DNA damage (XREF_FIG and XREF_SUPPLEMENTARY), suggesting that USP13 promotes RAP80 deubiquitination following DNA damage.
USP13 deubiquitinates BECN1. 9 / 9
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We demonstrate that USP10 and USP13 can both mediate the deubiquitination of Beclin1.

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Recent studies indicated that USP13 can deubiquitinate and regulate protein levels of Beclin-1, microphathalmia associated transcription factor, Siah2, phosphatase and tensin homolog, and STAT-1, and the deubiquitination process of USP13 could also be orchestrated by Beclin-1.

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While A20 inhibits PtdIns3P signaling by removing the TRAF6-dependent Lys63-linked chains from Beclin 1, the enzymes USP10 and USP13 prevent PI3K-III complex components from their degradation and, therefore, support autophagy. Interestingly enough, USP10 also stabilizes p53, which, in turn, triggers the degradation of Beclin 1 and VPS34 in order to prevent autophagy.

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It promotes the degradation of Vps34 complexes by inhibiting USP10 and USP13, two ubiquitin specific peptidases that target the deubiquitination of Beclin-1.

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USP10 and USP13 have been shown to mediate the deubiquitination of Beclin 1, thereby stabilizing the Vps34 complex XREF_BIBR.

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Likewise, USP13, which deubiquitinates BECN1 and stabilizes PIK3C3 complexes, is amplified in LUSQ.

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Conversely, it was show that Beclin 1 is deubiquitinated by USP10 and USP13 and adding complexity, Beclin 1 itself controlled the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities, in turn regulating the levels of tumor suppressor p53 [XREF_BIBR].

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Furthermore, the presence of spautin-1 inhibited the deubiquitination of Beclin1 mediated by USP10 and USP13.

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Specific and potent autophagy inhibitor-1 (Spautin-1) was identified to inhibit USP10 and USP13, which deubiquitinate the Beclin 1 subunit of Vsp34 complex, and thus promoted the degradation of Vsp34 PI3 kinase complex.
USP13 deubiquitinates PTEN. 8 / 8
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Wild-type USP13 purified from either bacteria or 293T cells, but not its catalytically inactive mutant C345A, decreased PTEN poly-ubiquitination by 64-70% in vitro (XREF_FIG).

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USP13 deubiquitinates and stabilizes PTEN.

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Deubiquitination and stabilization of PTEN by USP13.

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Deubiquitination of PTEN by USP13, a deubiquitinating enzyme, stabilized PTEN, and thereby inhibited breast cancer tumorigenesis [5].

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Deubiquitylation and stabilization of PTEN by USP13

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Therefore, USP13 can directly deubiquitinate PTEN.

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Deubiquitylation and stabilization of PTEN by USP13.

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On the other hand, ectopic expression of wild-type USP13, but not the C345A mutant which is still capable of interacting with PTEN (XREF_FIG), reduced the poly-ubiquitination of PTEN by 65% (XREF_FIG), suggesting that the enzymatic activity of USP13 is indispensable for USP13 dependent deubiquitination of PTEN.
USP13 deubiquitinates MCL1. 6 / 6
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USP13 interacts with and deubiquitinates Mcl-1 in cervical cancer cells.

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Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.

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USP13 interacts with and deubiquitinates MCL1.

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Two DUBs USP9X and USP13 deubiquitinate and stabilise MCL1, and hypomorphic mutations in both have been linked to neurodevelopmental disorders and neurodegenerative disease [XREF_BIBR, XREF_BIBR].

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Next, we confirmed that USP13 deubiquitinated Mcl-1.

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Therefore, USP13 interacted with and deubiquitinated MCL1 to preserve its protein stability.
USP13 deubiquitinates USP10. 5 / 5
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Moreover, beclin-1 and USP10 are involved in a potential feedforward mechanism in which beclin-1 stabilizes USP13, which in turn deubiquitinates and stabilizes USP10, leading to increased beclin-1 levels and activity.

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Since USP13 can also deubiquitinate USP10, regulating the stability of USP13 by Beclin1 provides a mechanism for Beclin1 to control the stability of USP10.

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These results suggest that USP13 may directly regulate the deubiquitination of USP10; however, USP10 may regulate USP13 indirectly perhaps by affecting the levels of Vps34 complexes.

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No evidence text available

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Consistent with this possibility, the ubiquitination levels of USP10 were reduced when cells were cotransfected with an expression vector of USP13 and the addition of spautin-1 inhibited the deubiquitination of USP10 by USP13 (XREF_FIG).
USP13 deubiquitinates MYC. 5 / 5
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Our data have demonstrated that USP13 mediates deubiquitination of c-Myc, whereas FBXL14 facilitates c-Myc ubiquitination in glioma cells.

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The ubiquitination assay demonstrated that disruption of USP13 by shRNA markedly increased c-Myc ubiquitination and reduced c-Myc protein level in GSCs (XREF_FIG).

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Furthermore, USP13 can deubiquitinate and stabilise ACLY and OGDH and c-Myc in ovarian cancer and glioblastoma, respectively, thereby functioning as an oncogene [XREF_BIBR, XREF_BIBR].

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Moreover, USP13 knockdown increased c-Myc ubiquitination, whereas FBXL14 knockdown reduced c-Myc ubiquitination (XREF_FIG).

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In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential.
USP13 deubiquitinates STAT1. 4 / 4
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Congruently, STAT1 ubiquitination is reduced in cells by USP13 overexpression and increased with USP13 knockdown regardless of IFNa treatment (115) .

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Congruently, STAT1 ubiquitination is reduced in cells by USP13 overexpression and increased with USP13 knockdown regardless of IFNα treatment (115).

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A recent report suggested that the deubiquitinase USP13 decreased STAT1 ubiquitination, which however was independent of IFNs treatment [XREF_BIBR].

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More specifically, USP13 positively regulates the antiviral activity of IFNa against DEN-2 virus replication by deubiquitinating and stabilizing STAT1 (115) .
USP13 deubiquitinates ACLY. 3 / 3
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USP13, the main regulator of ovarian cancer energy metabolism, specifically deubiquitinates and stabilizes oxoglutarate dehydrogenase and ATP citrate lyase, which can catalyze fatty acid synthesis, glutaminolysis and mitochondrial respiration.

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Furthermore, USP13 can deubiquitinate and stabilise ACLY and OGDH and c-Myc in ovarian cancer and glioblastoma, respectively, thereby functioning as an oncogene [XREF_BIBR, XREF_BIBR].

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USP13 directly deubiquitinates ACLY and OGDH.
USP13 deubiquitinates OGDH. 3 / 3
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USP13 directly deubiquitinates ACLY and OGDH.

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USP13, the main regulator of ovarian cancer energy metabolism, specifically deubiquitinates and stabilizes oxoglutarate dehydrogenase and ATP citrate lyase, which can catalyze fatty acid synthesis, glutaminolysis and mitochondrial respiration.

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Furthermore, USP13 can deubiquitinate and stabilise ACLY and OGDH and c-Myc in ovarian cancer and glioblastoma, respectively, thereby functioning as an oncogene [XREF_BIBR, XREF_BIBR].
USP13 deubiquitinates SIAH2. 2 / 2
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Besides phosphorylation, Siah2 activity can be modulated by the deubiquitinating enzyme USP13, which binds to and deubiquitinates Siah2, increasing its stability but diminishing its activity toward its substrates.

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The DUB USP13 regulates Siah2 availability and activity as deubiquitination of Siah2 by USP13 results in a more stable, albeit less active, ubiquitin ligase.
USP13 deubiquitinates nsp13. 2 / 2
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We found that nsp13 interacts with the deubiquitinase USP13, which deubiquitinates and stabilizes nsp13.

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Loss of USP13 enhances ubiquitination of nsp13 and destabilizes nsp13 protein.
USP13 deubiquitinates UBL4A. 2 / 2
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we identify USP13 as a gp78-associated DUB that eliminates ubiquitin conjugates from Ubl4A to maintain the functionality of Bag6.

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No evidence text available
USP13 leads to the deubiquitination of STING1. 2 / 2
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Consistently, reconstitution of USP13 but not USP13 (AE) into Usp13 m/m MEFs inhibited HSV-1-induced ubiquitination of STING (XREF_FIG).

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Here, we show that ubiquitin-specific protease 13 (USP13) is a STING-interacting protein that catalyses deubiquitination of STING.
Modified USP13 leads to the deubiquitination of MYC. 2 / 2
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Importantly, overexpression of USP13 together with FBXL14 abolished the increased c-Myc ubiquitination caused by FBXL14 overexpression (XREF_FIG, last lane).

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Overexpression of USP13 reduced c-Myc ubiquitination, and forced expression of FBXL14 increased c-Myc ubiquitination (XREF_FIG).
USP13 leads to the deubiquitination of Cohesin. 1 / 1
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Because ectopic overexpression of USP13 promoted deubiquitination of cohesin subunits, inactivation of USP13 was conversely expected to cause enhanced accumulation of ubiquitinated cohesin subunits.
USP13 deubiquitinates SKP2. 1 / 1
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No evidence text available
USP13 deubiquitinates VCL. 1 / 1
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Future studies are warranted to determine the ubiquitination of vinculin in 293T cell lines and whether USP13 deubiquitinates vinculin polyubiquitylation and stabilizes vinculin protein.
USP13 deubiquitinates MITF. 1 / 1
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However, deubiquitinase?USP13 can stabilize?MITF?expression and prolong its half‐life.
Modified mutated USP13 leads to the deubiquitination of MYC. 1 / 1
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Consistently, overexpression of the wild type but not the USP13 mutant reduced c-Myc ubiquitination and resulted in elevated c-Myc protein levels (XREF_FIG).
USP13 deubiquitinates SIGIRR. 1 / 1
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Stabilization of IL-1R8/Sigirr by USP13 describes a novel anti-inflammatory pathway in diseases that could provide a new strategy to modulate immune activation.
Modified USP13 leads to the deubiquitination of PTEN. 1 / 1
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On the other hand, ectopic expression of wild-type USP13, but not the C345A mutant which is still capable of interacting with PTEN (XREF_FIG), reduced the poly-ubiquitination of PTEN by 65% (XREF_FIG), suggesting that the enzymatic activity of USP13 is indispensable for USP13 dependent deubiquitination of PTEN.
Mutated USP13 deubiquitinates STING1. 1 / 1
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As expected, we found that USP13 but not the enzymatic inactive mutant USP13 (AE) catalysed deubiquitination of STING in cells or in vitro (XREF_FIG).
USP13 leads to the deubiquitination of Cohesin on T293. 1 / 1
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To investigate whether USP13 mediated the deubiquitination of cohesin subunits, we cotransfected 293T cells with expression vectors for His ubiquitin and Myc-USP13, purified ubiquitinated proteins by Ni-NTA affinity chromatography, and performed Western blot with antibodies to SMC3 and RAD21 (XREF_FIG A).
USP13 leads to the deubiquitination of AMFR. 1 / 1
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The proper function of BAG6 seems to require the activity of the deubiquitinating enzyme USP13, which antagonizes gp78 mediated ubiquitination to ensure ERAD efficiency.
USP13-C345A leads to the deubiquitination of ACLY. 1 / 1
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The C345A mutant of USP13 failed to reduce the ubiquitination of ACLY (XREF_FIG), suggesting that the deubiquitination activity is essential for the function of USP13.
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USP13 interacted with Snail to deubiquitinate and stabilize Snail in GC cells.
USP13 deubiquitinates SNAI1. 1 / 1
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USP13 interacted with Snail to deubiquitinate and stabilize Snail in GC cells.
USP13 leads to the deubiquitination of MYC. 1 / 1
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As USP13 functions as a deubiquitinase that also interacts with c-Myc (XREF_FIG) and the preferential expression of USP13 in GSCs positively regulates c-Myc protein levels (XREF_FIG), we hypothesized that USP13 might mediate deubiquitination of c-Myc protein to prevent its degradation and stabilize c-Myc in GSCs.

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP13 affects MCL1
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USP13 activates MCL1.
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USP13 activates MCL1. 10 / 15
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Taken together, our results indicated that pharmacological inhibition of USP13 by spautin-1 reduced MCL1 protein abundance and increased tumor cell sensitivity to ABT-263.

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The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer.

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These data demonstrate that USP13 promotes the stability of Mcl-1 in HPV+ cervical cancer cells by protecting it from proteasomal degradation.

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We subsequently investigated the impact of USP13 mediated MCL1 stabilization on tumor malignancy.

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Conversely, overexpression of WT USP13, but not the USP13 mutant, enhanced the half-life of Mcl-1 to ~ 300min.

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First, USP13 promoted MCL1 protein stability in multiple lung and ovarian cancer cell models.

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USP13 promotes MCL1 protein stability.

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Our data shows that USP13 and Mcl-1 protein expression correlates, suggesting that USP13 mediated Mcl-1 stabilisation is clinically relevant.

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USP13 promotes Mcl-1 stability.

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Finally, USP13 inhibition reduced MCL1 protein abundance and thereby increased tumor cell sensitivity to BH3 mimetic inhibitor ABT-263.
USP13 increases the amount of MCL1.
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USP13 increases the amount of MCL1. 5 / 5
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We confirmed the siRNA screen results by transfecting each of the four oligos against USP13 into HEK293T cells, and indeed found that USP13 knockdown decreased the endogenous protein levels of MCL1, while modulating USP9X or OTUB2 with different siRNAs had no consistent effects on MCL1 expression.

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Critically, treatment of USP13 depleted cells with the proteasome inhibitor MG132 rescued Mcl-1 protein levels, suggesting that USP13 protects Mcl-1 from proteasomal degradation.

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Loss of USP13 significantly reduced Mcl-1 protein expression, without effecting MCL1 mRNA expression.

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In addition, we explored whether pharmacological inhibition of USP13 downregulated MCL1 protein expression and synergistically kill tumor cells in combination with ABT-263.

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Interestingly, over-expression or depletion of USP13 did not modulate Mcl-1 expression in HPV- C33A cells, suggesting that Mcl-1 expression is not regulated by USP13 in these cells.
Mutated USP13 increases the amount of MCL1. 1 / 1
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This was dependant on the catalytic activity of USP13, as a catalytically inactive USP13 mutant did not increase Mcl-1 protein levels.
USP13 decreases the amount of MCL1.
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USP13 decreases the amount of MCL1. 2 / 2
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In addition, genetic depletion of USP13 using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9, or pharmacological inhibition of USP13 by a small-molecule inhibitor spautin-1, markedly downregulates MCL1 protein expression and shows synergistic effects against tumor cells in combination with ABT-263, a selective antagonist of BCL-2 and BCL-XL.

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Interestingly, although USP13 depletion reduced MCL1 protein levels, neither cell proliferation nor cell migration was significantly changed under normal growth conditions.
USP13 decreases the amount of ubiquitinated MCL1. 1 / 1
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Consistent with USP13 removing ubiquitin from MCL1, wild type USP13, but not catalytically inactive mutant USP13 C345A, markedly reduced the amount of ubiquitinated MCL1.
USP13-C345A decreases the amount of ubiquitinated MCL1. 1 / 1
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Consistent with USP13 removing ubiquitin from MCL1, wild type USP13, but not catalytically inactive mutant USP13 C345A, markedly reduced the amount of ubiquitinated MCL1.
USP13 inhibits MCL1.
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USP13 inhibits MCL1. 1 / 1
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Hence, pharmaceutical intervention of USP13 activity is expected to antagonize the tumorigenic potential of MCL1 oncoprotein, and combined administration of USP13 inhibitors with clinically approved venetoclax therapy may represent a promising targeting strategy for the treatment of human cancer by inducing tumor cell death.
USP13 affects PTEN
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USP13 increases the amount of PTEN.
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USP13 increases the amount of PTEN. 7 / 7
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Results suggested that the overexpression of NF-kB p65 significantly decreased the expression levels of USP13 and PTEN, and re-introduction of USP13 rescued PTEN expression.

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Furthermore, restoration of USP13 rescued PTEN expression, cell phenotypes and xenograft tumor growth which is altered by NF-kB activation.

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In addition, reintroduction of USP13 partially rescued PTEN expression as well as the oncogenesis trend caused by NF-kB.

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Our data revealed that knockdown of USP13 by short hairpin RNA (shRNA) significantly decreased PTEN protein expression in BC cells.

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Results indicated that USP13 knockdown notably decreased PTEN protein expression and increased phosphor-AKT levels in BC cells.

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Although each of these five DUBs could interact with endogenous PTEN (XREF_SUPPLEMENTARY), only one of them, USP13, significantly increased endogenous PTEN protein expression (XREF_SUPPLEMENTARY).

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Moreover, reintroduction of USP13 repressed the signaling transduction of NF-kB and largely rescued PTEN expression in NF-kB activated or miR-130b/301b overexpressed BC cells.
Modified USP13 increases the amount of PTEN. 2 / 2
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Collectively, these data suggest that loss of USP13 may contribute to loss of PTEN in a substantial fraction of human tumors, whereas in other tumors PTEN can be inactivated by different mechanisms, including genetic alterations and upregulation of PTEN ubiquitin ligases (such as NEDD4-1 14 and WWP2 15).

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Additionally, we noticed that in fibroblasts, the loss of USP13 down-regulated PTEN protein expression by increasing PTEN ubiquitination.
USP13 activates PTEN.
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USP13 activates PTEN. 2 / 6
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These data supported our notion that USP13 suppresses tumorigenesis by blocking the NF-kB-driven PTEN downregulation in BC.

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USP13 mediates PTEN to ameliorate osteoarthritis by restraining oxidative stress, apoptosis and inflammation via AKT dependent manner.
USP13 decreases the amount of PTEN.
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USP13 decreases the amount of PTEN. 3 / 4
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Reintroduction of USP13 could block the pathway and rescue PTEN protein expression, and thereby inhibited the carcinogenesis of bladder cells.

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Knockdown of USP13 by USP13 shRNA, miR-130b/301b overexpression or NF-kB activation in BC cells leads to the loss of PTEN expression, which was subsequently demonstrated to be reversed by reintroduction of USP13.

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Two independent USP13 shRNAs both decreased PTEN protein expression by 80% and increased phospho-AKT and phospho-FOXO1/3 levels by 3- to 5-fold in SUM159 breast cancer cells, while restoration of PTEN or expression of an RNAi resistant ' silence mutant ' (i.e., no amino acid change) of USP13 (USP13-RE) in USP13 depleted SUM159 cells completely reversed the effect of USP13 shRNA on upregulating the phosphorylation of AKT and FOXO (XREF_FIG and XREF_SUPPLEMENTARY).
Modified USP13 decreases the amount of PTEN. 2 / 2
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Overexpression of miR-130b/301b or USP13 knockdown by shRNA delivery decreases USP13 expression, and further reduces PTEN protein expression and leads to enhancement of cell proliferation, invasion and migration.

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Furthermore, USP13 overexpression induced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and repressed the activation of AKT as well as the expression of the downstream effectors glucose transporter-1 (GLUT1) and hexokinase-2 (HK2).
USP13 inhibits PTEN.
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USP13 inhibits PTEN. 2 / 4
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Conversely, overexpression of USP13 suppresses tumorigenesis and glycolysis in PTEN positive but not PTEN-null breast cancer cells.

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Down-regulation of USP13 mediates PTEN protein loss and fibroblast phenotypic change, and thereby plays a crucial role in IPF pathogenesis.

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USP13 knockdown in BC cells promoted their proliferation, invasion and migration.

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Meanwhile, silencing of USP13 greatly enhanced proliferation, invasion and migration of the tested cells.

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Treatment with afatinib alone diminished the number of proliferating cells to approximately 36%, while USP13 shRNA only slightly decreased cell proliferation.

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Depletion of USP13 inhibited cervical cancer cell proliferation.

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By contrast, KD of USP13 only modestly reduced proliferation of cell lines with low USP13 expression (SKOV3 and IGROV1) (XREF_FIG; XREF_SUPPLEMENTARY).

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In two other USP13 high HGSC cell lines (OAW28 and OVCAR3) XREF_BIBR, silencing USP13 also profoundly inhibited cell proliferation (XREF_SUPPLEMENTARY).

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Next, we treated infected THP-1 cells with a cell-permeable potent autophagy inhibitor, spautin-1.58 Spautin-1 promotes the degradation of BECN1 by inhibiting 2 USPs (ubiquitin-specific peptidases), USP10 and USP13, which target BECN1.58 Spautin-1 treatment of infected cells significantly decreased E. chaffeensis proliferation (Fig. 3B).

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miR-135b promoted cell proliferation and glycolysis that could be reversed by the overexpression of USP13 or PTEN.

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As a results, downregulation of USP13 dramatically inhibited A549 and H226 cell proliferation by AKT and MAPK signaling and suppressed tumor growth in nude mice.

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Overexpression of miR-130b/301b or USP13 knockdown by shRNA delivery decreases USP13 expression, and further reduces PTEN protein expression and leads to enhancement of cell proliferation, invasion and migration.

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Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage independent growth, glycolysis and tumor growth through downregulation of PTEN.

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Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage independent growth, glycolysis and tumour growth through downregulation of PTEN.

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Overexpression of miR-130b/301b or USP13 knockdown by shRNA delivery decreases USP13 expression, and further reduces PTEN protein expression and leads to enhancement of cell proliferation, invasion and migration.

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XREF_FIG, USP13 deficiency significantly increased fibroblast proliferation.

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In addition, USP13 disruption significantly reduced GSC proliferation (XREF_FIG) but showed little effects on NSTCs and NPCs (not depicted).

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Interestingly, despite the fact that the viral oncogenes do not regulate USP13 expression, depletion of USP13 in HPV- C33A cells did not cause a proliferation defect.

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In lung and ovarian cancers, where USP13 also regulates Mcl-1 stability, USP13 does not contribute to the cell proliferation of unstressed cells.

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Two independent USP13 shRNAs (XREF_FIG) both markedly increased the proliferation (XREF_FIG) and anchorage independent growth (XREF_FIG) of SUM159 breast cancer cells, while restoration of PTEN (XREF_FIG) or expression of an RNAi resistant USP13 mutant (XREF_SUPPLEMENTARY) completely reversed the effect of USP13 shRNA (XREF_FIG).

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Stable knockdown (KD) of USP13 by lentiviral short hairpin RNAs (shRNAs) markedly inhibited the proliferation of the USP13 amplified cell lines (CAOV3 and HeyA8) and the USP13 overexpressing cell line (OVCAR8).

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Further studies will be required to identify these targets and understand how they contribute to USP13 mediated cell proliferation.

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Next, USP13 knockdown prominently reduced the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of Hep3B and Huh7 cells, while USP13 overexpression enhanced these biological behaviors of HepG2 and LO2 cells.
USP13 affects MYC
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USP13 activates MYC.
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USP13 activates MYC. 2 / 8
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Collectively, these data demonstrate that the ubiquitination insensitive mutant of c-Myc is able to rescue the phenotypes caused by USP13 knockdown or FBXL14 overexpression in vitro and in vivo, which supports that USP13 and FBXL14 mediate posttranslational regulation of c-Myc to control the stem cell like phenotype and tumorigenic potential of GSCs.

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We found a positive correlation between TRF1 levels and all the stem cell markers with the exception of MYC, although TRF1 was positively correlated with the MYC modulator USP13 (Fang et al., 2017).
USP13 activates MYC. 2 / 2
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CHX chase assays indicated that overexpression of WT-USP13, particularly a phosphomimetic USP13-Y708E, but not USP-Y708F, significantly up-regulated the half-time of the c-Myc protein in HEK293 cells (XREF_FIG).

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In addition, IHC staining of Ki-67 and cleaved caspase 3 confirmed that USP13 disruption reduced c-Myc protein in the GSC derived xenografts and led to a significant decrease in cell proliferation and an increase in cell apoptosis within the tumor (not depicted).
USP13 bound to MYC activates MYC. 1 / 1
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As USP13 is a deubiquitinase, the interaction between USP13 and c-Myc led us to hypothesize that USP13 may stabilize c-Myc protein in GSCs through deubiquitination.
USP13-Y708F activates MYC. 1 / 1
| 1

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The expression of USP13-Y708E but not USP13 Y708F mutant significantly promoted the recruitment of c-Myc on the promoters of purine associated enzymes (XREF_FIG), consequently enhancing their expression (XREF_FIG).
USP13 increases the amount of MYC.
| 7
USP13 increases the amount of MYC. 5 / 5
| 5

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In vitro analysis showed inducible disruption of USP13 in GSCs by 70% reduced c-Myc protein levels and inhibited GSC proliferation (XREF_FIG).

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Targeting USP13 reduces c-Myc protein levels and impairs GSC maintenance.

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As USP13 functions as a deubiquitinase that also interacts with c-Myc (XREF_FIG) and the preferential expression of USP13 in GSCs positively regulates c-Myc protein levels (XREF_FIG), we hypothesized that USP13 might mediate deubiquitination of c-Myc protein to prevent its degradation and stabilize c-Myc in GSCs.

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In this study, we demonstrated that USP13 mediated deubiquitination and FBXL14 mediated ubiquitination regulate c-Myc protein levels in glioma cells and play a critical role in controlling the maintenance or differentiation of GSCs (XREF_FIG).

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The ubiquitination assay demonstrated that disruption of USP13 by shRNA markedly increased c-Myc ubiquitination and reduced c-Myc protein level in GSCs (XREF_FIG).
USP13 increases the amount of MYC. 1 / 1
| 1

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In HCC cell lines, knockdown of USP13 by shRNAs markedly decreased HCC cell growth, and mechanistic investigations revealed that USP13 knockdown could markedly downregulate the expression levels of c-Myc.
Modified USP13 increases the amount of MYC. 1 / 1
| 1

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In contrast, overexpression of USP13 (Flag-USP13) increased c-Myc protein levels in GSCs (XREF_FIG).
USP13 inhibits MYC.
| 1
USP13 inhibits MYC. 1 / 2
| 1

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Moreover, treatment with a proteasome inhibitor blocked the c-Myc loss caused by USP13 knockdown (not depicted), but overexpression of USP13 delayed c-Myc turnover in the presence of cycloheximide (not depicted), suggesting a critical role of USP13 in preventing proteasomal degradation of c-Myc in GSCs.
| 2 11
| 2 5

eidos
It is also noteworthy to point out that USP13 amplifications did not seem to increase B-cell infiltration in LUSC , which has the opposite effect on disease outcome [ 38 ] .
| PMC

eidos
USP13 knockdown prominently suppressed MGC-803 cell migration and invasion .

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Finally, Snail knockdown significantly blocked USP13-induced SGC-7901 cell migration and invasion.

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Next, USP13 knockdown prominently reduced the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of Hep3B and Huh7 cells, while USP13 overexpression enhanced these biological behaviors of HepG2 and LO2 cells.

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It is also noteworthy to point out that USP13 amplifications did not seem to increase B-cell infiltration in LUSC, which has the opposite effect on disease outcome [38].
| PMC

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USP13 knockdown prominently suppressed MGC-803 cell migration and invasion.

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On the other hand, although USP13 arm-level gains and high amplifications significantly increased lymphocyte infiltration in HNSC, OV and STAD, higher USP13 levels were correlated with shorter survival in ovarian and gastric cancers.
| PMC

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Meanwhile, silencing of USP13 greatly enhanced proliferation, invasion and migration of the tested cells.

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Overexpression of miR-130b/301b or USP13 knockdown by shRNA delivery decreases USP13 expression, and further reduces PTEN protein expression and leads to enhancement of cell proliferation, invasion and migration.

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Results suggested that overexpression of NF-kB p65 greatly increased the number of migrated and invaded cells, however knockdown of miR-130b/301b or restoration of USP13 rescued the increased cell invasion and migration caused by NF-kB activation.

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USP13 knockdown in BC cells promoted their proliferation, invasion and migration.
| 1

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Overexpression of miR-130b/301b or USP13 knockdown by shRNA delivery decreases USP13 expression, and further reduces PTEN protein expression and leads to enhancement of cell proliferation, invasion and migration.

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The in vivo experiments finally confirmed that USP13 dramatically repressed synovial hyperplasia, inflammatory cell infiltration, cartilage damage and bone loss in collagen induced arthritis (CIA) mice via the same molecular mechanisms detected in vitro.
Spautin-1 affects USP13
1 | 2 9
1 | 2 9

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Spautin-1 inhibits the activity of the deubiquitinating enzymes USP13 and USP10.

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Spautin-1 inhibits the catalytic activity of both USP10 and USP13 with an IC 50 of ~ 0.6-0.7 microM.

tas
No evidence text available

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Spautin-1 inhibits the activity of two ubiquitin specific peptidases, USP10 and USP13, causing an increase in proteasomal degradation of class III PI3 kinase complexes, which have been shown to regulate autophagy [XREF_BIBR].

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Spautin-1 promotes the degradation of PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3, also termed Vps34 in yeast) complexes by inhibiting USP10 (ubiquitin specific peptidase 10) and USP13 (ubiquitin specific peptidase 13).

eidos
Spautin-1 also reduced USP13 expression , as has been previously observed in other cell lines ( Fig. 8A ) .

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Indeed, a recent study showed that a small molecule, Spautin-1, promoted the degradation of Vps34 by inhibiting two ubiquitin specific proteases USP10 and USP13 that regulate the stability of the Vps34 complex [XREF_BIBR].

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Spautin-1 inhibits ubiquitin specific peptidases, USP10 and USP13, and promotes the degradation of Vps34-PI3 kinase complexes, key regulators of autophagy, leading to inhibition of autophagy.

eidos
In both HeLa and SiHa cells , inhibition of USP13 by Spautin-1 resulted in a dose-dependent decrease in Mcl-1 protein expression ( Fig. 8A ) .

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58 Spautin-1 promotes the degradation of BECN1 by inhibiting 2 USPs (ubiquitin-specific peptidases), USP10 and USP13, which target BECN1.
USP13 affects OGDH
| 7
USP13 activates OGDH.
| 2
USP13 activates OGDH. 2 / 4
| 2

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Next, we examined whether USP13 augments the stability of ACLY and OGDH.

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USP13 upregulates ACLY and OGDH, two key regulators that drive glutaminolysis, ATP generation and lipid synthesis in cancer metabolism.
USP13 inhibits OGDH.
| 2
USP13 inhibits OGDH. 2 / 3
| 2

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These data suggest that USP13-KD induces mitochondrial dysfunction and lipogenic dysfunction by reducing OGDH and ACLY activity, thereby reducing glutamine 's reductive carboxylation and glucose 's oxidation for lipid synthesis (XREF_FIG).

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Depletion of USP13 markedly decreased protein stability of ACLY and OGDH (XREF_FIG; XREF_SUPPLEMENTARY), but had no effect on the transcription of ACLY and OGDH (XREF_FIG).
USP13 decreases the amount of OGDH.
| 2
USP13 decreases the amount of OGDH. 1 / 2
| 1

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We proposed that KD of USP13 reduces OGDH expression thereby limiting the synthesis of TCA cycle intermediates from oxidative pathways (XREF_FIG).
Modified USP13 decreases the amount of OGDH. 1 / 1
| 1

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Overexpression of USP13 markedly reduced the levels of ubiquitinated ACLY and OGDH (XREF_FIG), suggesting that USP13 may stabilize ACLY and OGDH through deubiquitination.
USP13 increases the amount of OGDH.
| 1
USP13-C345A increases the amount of OGDH. 1 / 1
| 1

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We found that the C345A mutant of USP13 was unable to increase the steady-state levels of ACLY and OGDH in contrast to the wild-type USP13 (XREF_FIG).
USP13 affects EGFR
| 11
USP13 inhibits EGFR.
| 5
USP13 inhibits mutated EGFR. 3 / 3
| 3

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We demonstrate that USP13 targeting leads to an increased sensitivity toward EGFR inhibition by both osimertinib and afatinib in NSCLC harboring the most common EGFR mutations (DeltaE746-A750 and L858R and T790M) while sparing EGFR wild-type cells and tumors.

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Overall, we showed that USP13 abrogates sorting and degradation of ubiquitinated mutant EGFR, independent of its catalytic activity but requiring its UBA domains that are known to bind to K63-type ubiquitin chains preferentially.

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23 In HEK293T cells expressing EGFR-DeltaE740-A746, USP13 antagonized the destabilization of mutant EGFR mediated by c-Cbl or Cbl-b.
USP13 inhibits EGFR. 2 / 2
| 2

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38, 39 Given that USP13 targeting caused EGFR destabilization, some of the effects may be independent of the EGFR kinase activity as EGFR can suppress cell death in manners that are independent of its kinase activity.

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Moreover, USP13 inhibition and silencing lead to a decreased half-life of the mutant EGFR protein in NSCLC cells, indicating that USP13 likely stabilizes EGFR.
USP13 activates EGFR.
| 5
USP13 activates mutated EGFR. 4 / 4
| 4

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Targeting USP13 mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non small cell lung cancer.

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Combined targeting of USP13 and EGFR strongly reduces the viability of EGFR mutant lung cancer cells in vitro and in vivo while sparing non malignant (EGFR wild-type) lung epithelial cells.

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37 USP13 is likely to stabilize mutant EGFR in a ubiquitinated state, and inhibition of USP13 destabilizes mutant EGFR and abrogates signaling of mutant EGFR in lung cancer cells.

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We found that USP13 inhibits mutant EGFR degradation by a process that leads to the accumulation of ubiquitinated (K48 and K63) EGFR, which is bound to c-Cbl and USP13.
USP13 activates EGFR. 1 / 1
| 1

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Targeting USP13 mediated drug tolerance increases the efficacy of EGFR inhibition of mutant EGFR in non small cell lung cancer.
USP13 decreases the amount of EGFR.
| 1
USP13 decreases the amount of EGFR. 1 / 1
| 1

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USP13 downregulation with siRNA decreased the total protein levels of EGFR, indicating a clear connection between USP13 expression and EGFR protein levels.
USP13 affects ACLY
| 7
USP13 activates ACLY.
| 3
USP13 activates ACLY. 3 / 6
| 3

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USP13-KD also significantly decreased ACLY activity, while USP13 overexpression enhanced ACLY activity in the ACLY activity assay (XREF_SUPPLEMENTARY).

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Next, we examined whether USP13 augments the stability of ACLY and OGDH.

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USP13 upregulates ACLY and OGDH, two key regulators that drive glutaminolysis, ATP generation and lipid synthesis in cancer metabolism.
USP13 inhibits ACLY.
| 2
USP13 inhibits ACLY. 2 / 2
| 2

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These data suggest that USP13-KD induces mitochondrial dysfunction and lipogenic dysfunction by reducing OGDH and ACLY activity, thereby reducing glutamine 's reductive carboxylation and glucose 's oxidation for lipid synthesis (XREF_FIG).

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Depletion of USP13 markedly decreased protein stability of ACLY and OGDH (XREF_FIG; XREF_SUPPLEMENTARY), but had no effect on the transcription of ACLY and OGDH (XREF_FIG).
USP13 increases the amount of ACLY.
| 1
USP13-C345A increases the amount of ACLY. 1 / 1
| 1

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We found that the C345A mutant of USP13 was unable to increase the steady-state levels of ACLY and OGDH in contrast to the wild-type USP13 (XREF_FIG).
USP13 decreases the amount of ACLY.
| 1
Modified USP13 decreases the amount of ubiquitinated ACLY. 1 / 1
| 1

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Overexpression of USP13 markedly reduced the levels of ubiquitinated ACLY and OGDH (XREF_FIG), suggesting that USP13 may stabilize ACLY and OGDH through deubiquitination.
JUN affects USP13
9 |
JUN decreases the amount of USP13. 9 / 9
9 |

biopax:msigdb
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biopax:msigdb
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biopax:msigdb
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biopax:msigdb
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biopax:msigdb
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biopax:msigdb
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biopax:msigdb
No evidence text available

biopax:msigdb
No evidence text available

biopax:msigdb
No evidence text available
USP13 affects SIAH2
| 5
USP13 activates SIAH2. 5 / 8
| 5

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Different forms of stress modulate these activities : hypoxia reduces USP13 expression enabling increased Siah2 activity, while cellular stress induces p38 activity and alters Siah localization, affec[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Conversely, inhibition of USP13 expression with corresponding shRNA decreases the stability of both Siah2 and its substrate Spry2.

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Overexpression of USP13 increases Siah2 stability by attenuating its autodegradation.

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Different forms of stress modulate these activities : hypoxia reduces USP13 expression enabling increased Siah2 activity, while cellular stress induces p38 activity and alters Siah localization, affecting its recognition and targeting of substrates 174.

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In melanoma cells, USP13 attenuates the autodegradation of Siah2, a RING (really interesting new gene) finger family E3 ubiquitin ligase.

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Indeed, knockdown of USP13 increased glucose uptake and glycolysis, which could be fully reversed by restoration of PTEN, as gauged by lactate production and glucose incorporation assays (XREF_FIG).

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In this study, we identified USP13 as the first deubiquitinase that reverses PTEN poly-ubiquitination and stabilizes PTEN protein, and found that USP13 suppresses tumorigenesis and glycolysis through PTEN.

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miR-135b promoted cell proliferation and glycolysis that could be reversed by the overexpression of USP13 or PTEN.

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Conversely, overexpression of USP13 suppresses tumorigenesis and glycolysis in PTEN positive but not PTEN-null breast cancer cells.
Modified USP13 inhibits glycolytic process. 2 / 2
| 2

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Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage independent growth, glycolysis and tumor growth through downregulation of PTEN.

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Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage independent growth, glycolysis and tumour growth through downregulation of PTEN.
USP13 affects MITF
| 4
USP13 activates MITF.
| 2
USP13 activates MITF. 2 / 3
| 2

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On the other hand, overexpression of the deubiquitinase USP13, which has been identified as a key regulator of MITF turnover, can enhance the basal half-life of the MITF protein to up to 4h (Zhao etal., 2011).

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More recently, it was shown that MITF is targeted by the de-ubiquitinase USP13, a theoretically drug-able protease whose suppression results in strong downregulation of MITF protein levels.
USP13 increases the amount of MITF.
| 2
USP13 increases the amount of MITF. 1 / 2
| 1

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By modulate the expression of MITF downstream genes, USP13 appeared to be essential for melanoma growth both in vivo and in vitro, indicating the possibility of targeting USP13 for melanoma therapy.
Modified USP13 increases the amount of MITF. 1 / 1
| 1

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Overexpression of USP13 in melanoma cells prolonged the half-time of MITF expression in an enzymatic dependent manner.
USP13 affects USP13
| 1 4
USP13 decreases the amount of USP13.
| 3
USP13 decreases the amount of USP13. 2 / 2
| 2

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We found that both USP13 shRNAs reduced USP13 expression in vivo compared to the control shRNA although with different efficiencies.

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Moreover, treatment with a proteasome inhibitor blocked the c-Myc loss caused by USP13 knockdown (not depicted), but overexpression of USP13 delayed c-Myc turnover in the presence of cycloheximide (not depicted), suggesting a critical role of USP13 in preventing proteasomal degradation of c-Myc in GSCs.
Modified USP13 decreases the amount of USP13. 1 / 1
| 1

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Overexpression of miR-130b/301b or USP13 knockdown by shRNA delivery decreases USP13 expression, and further reduces PTEN protein expression and leads to enhancement of cell proliferation, invasion and migration.
USP13 activates USP13.
| 1
USP13 activates USP13. 1 / 2
| 1

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( D ) Hypoxia increased USP13 , TLR4 , MyD88 , and P-NF-kappaB p65 proteins , which was subsequently reduced by USP13 knockdown .
USP13 inhibits USP13.
| 1
Mutated USP13 inhibits USP13. 1 / 1
| 1

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Two independent USP13 shRNAs (XREF_FIG) both markedly increased the proliferation (XREF_FIG) and anchorage independent growth (XREF_FIG) of SUM159 breast cancer cells, while restoration of PTEN (XREF_FIG) or expression of an RNAi resistant USP13 mutant (XREF_SUPPLEMENTARY) completely reversed the effect of USP13 shRNA (XREF_FIG).
| 1 4

eidos
USP13 suppression induces apoptosis upon EGFR inhibition of mutant NSCLC cells USP13 downregulation or inhibition severely compromised the viability of PC9 and HCC827 cells when cotreated with afatinib .

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In addition, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) assay demonstrated that expression of the mutant c-Myc diminished the increased apoptosis caused by USP13 disruption in GSC derived xenografts (not depicted).

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We then showed that over-expressing USP13 markedly suppressed inflammatory response, oxidative stress and apoptosis in H-FLSs upon IL-1beta or TNF-alpha challenge, whereas USP13 knockdown exhibited detrimental effects.

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3.3 USP13 suppression induces apoptosis upon EGFR inhibition of mutant NSCLC cells.

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However, in the context of hypoxic or oxidative stresses, USP13 loss caused a substantial decrease of cell viability and a significant increase of cell apoptosis in both TOV-21G and SW-1573 tumor models.
| 2 3
USP13 increases the amount of extracellular matrix.
| 3
USP13 increases the amount of extracellular matrix. 3 / 3
| 3

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To investigate the molecular mechanisms by which USP13 modulates ECM expression, we focused on the role of USP13 on Smad4 expression.

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The results indicate that USP13 promotes ECM expression by stabilizing Smad4 in lung fibroblasts and plays a role in the maintenance of the extracellular matrix in lungs.

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The reductions in both protein levels and mRNA expression of ECM were observed in the isolated lung fibroblasts from USP13 deficient mice, suggesting that downregulation of USP13 reduces ECM levels through inhibiting its transcription.
| 2

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The results indicate that USP13 promotes ECM expression by stabilizing Smad4 in lung fibroblasts and plays a role in the maintenance of the extracellular matrix in lungs .

eidos
To investigate the molecular mechanisms by which USP13 modulates ECM expression , we focused on the role of USP13 on Smad4 expression .
USP13 affects VCL
| 5
USP13 increases the amount of VCL.
| 4
USP13 increases the amount of VCL. 4 / 4
| 4

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USP13 upregulates vinculin protein levels, but not mRNA levels.

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Among the identified proteins, the vinculin protein level was upregulated by USP13 through an enzymatically mediated mechanism, which was confirmed by western blot analysis and RT-qPCR.

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These results suggest that USP13 upregulates vinculin protein levels, but not the mRNA levels, through an enzymatically mediated mechanism.

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To further validate the upregulation of vinculin protein levels by USP13, western blot analysis and RT-qPCR analysis were performed.
USP13 activates VCL.
| 1
USP13 activates VCL. 1 / 1
| 1

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In this study, 2D-DIGE was used to explore whether vinculin is upregulated by USP13.
USP13 affects BECN1
| 5
USP13 activates BECN1.
| 4
USP13 activates BECN1. 4 / 4
| 4

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This molecule promotes the degradation of Vps34-PI 3 kinase complexes by inhibiting two ubiquitin specific peptidases, USP10 and USP13, that target the Beclin-1 subunit of Vps34 complexes.

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XREF_BIBR Spautin-1 promotes the degradation of BECN1 by inhibiting 2 USPs (ubiquitin specific peptidases), USP10 and USP13, which target BECN1.

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Spautin-1, a potent small molecule, can promote the degradation of PI3KCIII and Vps34 complexes by inhibiting two ubiquitin specific peptidases, USP10 and USP13 which target the Beclin-1 subunit of Vp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Spautin-1 has been recently reported to prevent autophagy by inhibiting the deubiquitinases USP10 and USP13, which leads to beclin 1 and Vps34 (or PI3KIII) degradation [XREF_BIBR].
USP13 increases the amount of BECN1.
| 1
USP13 increases the amount of BECN1. 1 / 1
| 1

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Moreover, beclin-1 and USP10 are involved in a potential feedforward mechanism in which beclin-1 stabilizes USP13, which in turn deubiquitinates and stabilizes USP10, leading to increased beclin-1 levels and activity.
USP13 affects glucose
| 5
USP13 inhibits glucose.
| 3
| 3

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Indeed, knockdown of USP13 increased glucose uptake and glycolysis, which could be fully reversed by restoration of PTEN, as gauged by lactate production and glucose incorporation assays (XREF_FIG).

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Therefore, USP13-KD also decreases glucose oxidation into TCA cycle metabolites.

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Functional studies demonstrated that overexpression of USP13 suppressed OSCC cell proliferation, glucose uptake and lactate production in vitro and inhibited tumor growth in vivo.
USP13 increases the amount of glucose.
| 1
Modified USP13 increases the amount of glucose. 1 / 1
| 1

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Furthermore, USP13 overexpression induced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and repressed the activation of AKT as well as the expression of the downstream effectors glucose transporter-1 (GLUT1) and hexokinase-2 (HK2).
USP13 decreases the amount of glucose.
| 1
Modified USP13 decreases the amount of glucose. 1 / 1
| 1

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Furthermore, USP13 overexpression induced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and repressed the activation of AKT as well as the expression of the downstream effectors glucose transporter-1 (GLUT1) and hexokinase-2 (HK2).
PIK3C3 affects USP13
| 5
PIK3C3 inhibits USP13.
| 2
PIK3C3 inhibits USP13. 2 / 2
| 2

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Using an imaging-based screen, Liu et al. (2011) recently identified a highly potent small molecule inhibitor of autophagy they named spautin-1 (specific and potent autophagy inhibitor 1), which promotes degradation of the Vps34 complexes via inhibiting ubiquitin-specific processing protease 10 (USP10) and USP13, two ubiquitin-specific peptidases that target the deubiquitination of Beclin1.2.

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It is interesting to note that the knock-down of VPS34 and BECLIN 1 also causes the degradation of USP10 and USP13, which indicates the existence of a regulatory feedback loop [XREF_BIBR].
PIK3C3 activates USP13.
| 2
PIK3C3 activates USP13. 2 / 2
| 2

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Another interesting observation made in the Spautin-1 study is that knock-down of VPS34 and Beclin 1 causes instability of USP10 and USP13, which indicates the existence of a regulatory feedback loop [XREF_BIBR].

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The close functional interconnection between the central PI3K-III subunits and the DUBs is demonstrated by the interesting observation that knock-down of VPS34 and Beclin 1 causes instability of USP10 and USP13, which strongly indicates the existence of a regulatory feedback loop [XREF_BIBR].
PIK3C3 increases the amount of USP13.
| 1
PIK3C3 increases the amount of USP13. 1 / 1
| 1

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Unexpectedly, we found that the knockdown of Beclin1 or Vps34 could also reduce the endogenous levels of USP10 and USP13 (XREF_FIG).
BECN1 affects USP13
| 5
BECN1 activates USP13.
| 3
BECN1 activates USP13. 3 / 3
| 3

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The close functional interconnection between the central PI3K-III subunits and the DUBs is demonstrated by the interesting observation that knock-down of VPS34 and Beclin 1 causes instability of USP10 and USP13, which strongly indicates the existence of a regulatory feedback loop [XREF_BIBR].

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Taken together, these results suggest that Beclin1 is the primary target of USP10 and USP13.

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Another interesting observation made in the Spautin-1 study is that knock-down of VPS34 and Beclin 1 causes instability of USP10 and USP13, which indicates the existence of a regulatory feedback loop [XREF_BIBR].
BECN1 inhibits USP13.
| 1
BECN1 inhibits USP13. 1 / 1
| 1

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It is interesting to note that the knock-down of VPS34 and BECLIN 1 also causes the degradation of USP10 and USP13, which indicates the existence of a regulatory feedback loop [XREF_BIBR].
BECN1 increases the amount of USP13.
| 1
BECN1 increases the amount of USP13. 1 / 1
| 1

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Unexpectedly, we found that the knockdown of Beclin1 or Vps34 could also reduce the endogenous levels of USP10 and USP13 (XREF_FIG).
USP13 affects cell
| 4
USP13 activates cell. 4 / 4
| 4

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Notably , USP13 knockdown repressed hypoxia-induced activation of the TLR4 / MyD88 / NF-kappaB pathway in HCC cells .

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Significantly , USP13 knockdown inhibited hypoxia-induced activation of the TLR4 / MyD88 / NF-kappaB pathway in HCC cells .

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Interestingly , the USP13 knockdown repressed the hypoxia-induced activation of the TLR4 / MyD88 / NF-kappaB pathway in HCC cells ( Figure 7D ) .

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USP13 knockdown inhibits the proliferation of HCC cells .
USP13 affects AMFR
| 1
USP13 inhibits AMFR. 1 / 4
| 1

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Because the accumulation of Bag6 * upon USP13 depletion is significantly reduced in cells co-depleted of USP13 and gp78 (XREF_FIG), we propose that USP13 is required to antagonize a promiscuous activity of gp78 towards Ubl4A, which would otherwise impair the function of the Bag6 complex by altering its interaction pattern and/or increasing its cleavage by a cellular protease.
USP13 affects Ubiquitin
| 4
| 3

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3.5 USP13 inhibits the ubiquitin mediated degradation of mutant EGFR.

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USP13 interacted with TLR4 and inhibited the ubiquitin mediated degradation of TLR4.

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In a cell study, USP5 and USP13 were found to degrade ubiquitin chains inside stress granules, defined as clumps of protein or RNA created when cells are stressed [XREF_BIBR].
USP13 bound to TLR4 inhibits Ubiquitin. 1 / 1
| 1

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USP13 interacted with TLR4 and inhibited the ubiquitin mediated degradation of TLR4.
USP13 affects SNAI1
| 4
USP13 activates SNAI1.
| 3
USP13 activates SNAI1. 3 / 3
| 3

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In conclusion, USP13 overexpression was frequently detected in GC and contributed to the EMT and metastasis of GC by stabilizing Snail.

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Deubiquitinase USP13 promotes the epithelial-mesenchymal transition and metastasis in gastric cancer by maintaining Snail protein.

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Mechanistically, USP13 knockdown promoted Snail degradation, which could be blocked by the proteasome inhibitor MG132.
USP13 increases the amount of SNAI1.
| 1
USP13 increases the amount of SNAI1. 1 / 1
| 1

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Interestingly, USP13 remarkably enhanced Snail protein expression but did not affect its mRNA levels in GC cells.
Ubiquitin affects USP13
| 1 2
| 1 2

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Domain swapping confers USP13 the ability to be activated by Ub.

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Since the ZnF domain of USP13 is not the Ub receptor, it is crucial to examine whether USP13 could be catalytically activated by Ub.

sparser
Since the ZnF domain of USP13 is not the Ub receptor, it is crucial to examine whether USP13 could be catalytically activated by Ub.
USP13 affects afatinib
| 1 2
| 1 2

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Overall, these data indicate that targeting of USP13 strongly potentiates the anticancer effects of afatinib in vivo.

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Similar results were obtained in HCC827 cells, confirming that USP13 knockdown strongly enhances afatinib in treatment-naive lung cancer cell lines.

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Similar results were obtained in HCC827 cells ( Figure 2D ) , confirming that USP13 knockdown strongly enhances afatinib in treatment-naive lung cancer cell lines .
USP13 affects Interferon
| 3
| 3

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However, USP13, USP19, and USP22 inhibit virus-induced IFN production by removing K27-linked polyubiquitin chains from STING (40, 81) or TRIF (90).

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USP13 has been reported to deubiquitinate and stabilize STAT1 and promote interferon (IFN)-induced signalling XREF_BIBR.

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Thus, USP13 positively regulates type I and type II IFN signaling by deubiquitinating and stabilizing STAT1 protein.
MYC affects USP13
| 1
MYC activates USP13. 1 / 3
| 1

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We found a positive correlation between TRF1 levels and all the stem cell markers with the exception of MYC, although TRF1 was positively correlated with the MYC modulator USP13 (Fang et al., 2017).
3 |
Benzo[a]pyrene decreases the amount of USP13.
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Benzo[a]pyrene decreases the amount of USP13. 2 / 2
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ctd
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ctd
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Benzo[a]pyrene increases the amount of USP13.
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Benzo[a]pyrene increases the amount of USP13. 1 / 1
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ctd
No evidence text available
USP13 affects Proteasome
| 3
USP13 activates Proteasome.
| 2
| 2

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Notably, USP13 not only bound Bag6, but also interacted with MMS1 and alpha6, subunits of the proteasome (lane 5), further implicating USP13 in delivery pathways that targets substrates to the proteasome.

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USP13 is upregulated in Alzheimer's disease (AD) and Parkinson's disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration.
USP13 inhibits Proteasome.
| 1
| 1

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USP13 knockdown significantly increased the activity of the 20S proteasome and reduced the levels of hyper-phosphorylated tau (p-tau) in primary cortical neurons.
USP13 affects NFkappaB
| 1 2
USP13 inhibits NFkappaB.
| 1 1
| 1 1

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USP13 suppresses NF-kB to promote PTEN expression , resulting in antitumor activity [ 65 ] .

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USP13 suppresses NF-kB to promote PTEN expression, resulting in antitumor activity [XREF_BIBR].
USP13 activates NFkappaB.
| 1
| 1

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Nonetheless, USP13 was not able to fully rescue the oncogenic function of NF-kB on BC cells, suggesting the possible involvement of other pathways in the process.
USP13 affects AKT
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USP13 activates AKT.
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USP13 activates AKT. 1 / 2
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Wu et al demonstrate that amplification of USP13 in some NSCLC leads to enhanced AKT and MAPK signaling that sustains cancer progression .
USP13 inhibits AKT.
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USP13 inhibits AKT. 1 / 1
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We conclude from these data that USP13 inhibits AKT signaling through positive regulation of PTEN protein.
NFkappaB affects USP13
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NFkappaB decreases the amount of USP13.
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Modified NFkappaB decreases the amount of USP13. 1 / 1
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Overexpression of NF-kB subunit p65 reduces protein expression of USP13 and PTEN.
NFkappaB decreases the amount of USP13. 1 / 1
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Our data demonstrated that NF-kB activation decreased expression level of USP13 and PTEN, and promoted the tumorigenesis phenotypes of BC cells.
NFkappaB activates USP13.
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Thus, we sought to find if USP13 could be targeted by NF-kB and miR-130b ~ 301b signaling and further facilitate the loss of PTEN.
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Valproic acid decreases the amount of USP13. 2 / 2
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No evidence text available

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Phenylmercury acetate decreases the amount of USP13. 2 / 2
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No evidence text available

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No evidence text available
Doxycycline affects USP13
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In vivo bioluminescent analysis confirmed that induced disruption of USP13 by doxycycline treatment significantly inhibited GSC tumor growth in mouse intracranial xenografts (XREF_FIG).

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To further confirm the clinical relevance of targeting USP13 in established GBM tumors, we applied the Tet-on inducible knockdown system to examine whether inducible disruption of USP13 by doxycycline affects the growth of established xenograft tumors and animal survival.
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Different forms of stress modulate these activities : hypoxia reduces USP13 expression enabling increased Siah2 activity, while cellular stress induces p38 activity and alters Siah localization, affec[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Different forms of stress modulate these activities : hypoxia reduces USP13 expression enabling increased Siah2 activity, while cellular stress induces p38 activity and alters Siah localization, affecting its recognition and targeting of substrates 174.