USP5 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 5
HGNC Gene Symbol
USP5
Identifiers
hgnc:12628 NCBIGene:8078 uniprot:P45974
Orthologs
mgi:1347343 rgd:1308438
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP5
Number of Papers
127 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
HSPE1 heat shock protein family E (Hsp10) member 1 0.401 -0.04 -0.28 6.18e-01
RAN RAN, member RAS oncogene family 0.397 0.50 2.64 1.05e-22
PSMD7 proteasome 26S subunit, non-ATPase 7 0.392 INDRA (1) Reactome (4) 0.29 1.51 9.79e-08
CHEK1 checkpoint kinase 1 0.391 0.38 2.01 1.11e-12
SARS1 seryl-tRNA synthetase 1 0.391 Reactome (1) 0.47 2.51 2.51e-20
ANAPC4 anaphase promoting complex subunit 4 0.384 -0.03 -0.28 6.23e-01
NEDD1 NEDD1 gamma-tubulin ring complex targeting factor 0.373 0.26 1.32 3.87e-06

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP5using 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:1901987 regulation of cell cycle phase transition Biological Process 1.31e-05 3.93e-03 1.97e-03
GO:1902749 regulation of cell cycle G2/M phase transition Biological Process 4.86e-05 1.46e-02 3.65e-03
GO:0044839 cell cycle G2/M phase transition Biological Process 9.46e-05 2.84e-02 4.09e-03
GO:0140014 mitotic nuclear division Biological Process 1.09e-04 3.26e-02 4.09e-03

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP5 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
UBC ubiquitin C 3.77e-01 1.14e-09 2.51e-05

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 USP5 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
USP5 leads to the deubiquitination of MAF. 4 / 4
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Because USP5, as a deubiquitinase of c-Maf, binds to and suppresses c-Maf polyubiquitination, we sought to determine whether mebendazole could interfere with the association of c-Maf and USP5.

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Consistent with the high level of c-Maf protein in MM cells, USP5 was also highly expressed.

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C-Maf ubiquitination can be reversed by the deubiquitinase USP5 because USP5 prevents c-Maf from polyubiquitination and degradation [XREF_BIBR].

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C-Maf ubiquitination can be reversed by the deubiquitinase USP5 because USP5 prevents c-Maf from polyubiquitination and degradation [8].
USP5 leads to the deubiquitination of SNAI2. 3 / 3
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Formononetin targets USP5 to inhibit the deubiquitination of SLUG.

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Collectively, these results indicated that USP5 promotes SLUG stabilization by deubiquitinating SLUG.

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USP5 interacts with and stabilizes SLUG to regulate its abundance through USP5 deubiquitination activities in epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC).
USP5 leads to the deubiquitination of CACNA1H. 2 / 2
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Knockdown of USP5 via shRNA increases Cav3.2 ubiquitination, decreases Cav3.2 protein levels, and reduces Cav3.2 whole-cell currents.

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USP5 deubiquitinates TP53. 2 / 2
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Review

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USP5 deubiquitinates p53 [XREF_BIBR], while USP2a acts on Mdm2 [XREF_BIBR], and differences in the levels of the two proteases can affect p53 levels.
Modified USP5 leads to the deubiquitination of FOXM1. 1 / 1
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Overexpression of USP5 reduces the endogenous ubiquitination of FoxM1 and increases FoxM1 expression [25].
USP5 deubiquitinates MAFA. 1 / 1
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Notably, MafA and MafB are also members of the c-Maf family, however, USP5 failed to deubiquitinate MafA, suggesting its substrate specificity.
USP5 deubiquitinates CTNNB1. 1 / 1
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Mechanistically, we found that USP5 deubiquitinated beta-catenin, prevented ubiquitination mediated beta-catenin degradation and promoted beta-catenin nuclear accumulation, leading to the activation of Wnt and beta-catenin signal pathway in NSCLC cells.
USP5 deubiquitinates STING1. 1 / 1
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In addition, the ubiquitination of STING was impaired by USP5, USP13, and USP22.
USP5 deubiquitinates CD274. 1 / 1
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USP5 directly interacted with PD-L1 and deubiquitinated PD-L1, therefore enhances PD-L1 protein stability.
USP5 leads to the deubiquitination of Proteasome. 1 / 1
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Interestingly, we also discovered that the human gene encoding the ubiquitin specific peptidase 5 (USP5), which is known to promote cellular deubiquitination and ubiquitin and proteasome dependent proteolysis, was a direct transcriptional target for miR-125a to repress.
USP5 desumoylates AXIN1. 1 / 1
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In the present manuscript, we demonstrate that SENP7S is a functional SUMO isopeptidase that deSUMOylates β-catenin and Axin1.
USP5 deubiquitinates TUFM. 1 / 1
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USP5 deubiquitinated TUFM and increased its level in CRC cells.
USP5 desumoylates CTNNB1. 1 / 1
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In the present manuscript, we demonstrate that SENP7S is a functional SUMO isopeptidase that deSUMOylates β-catenin and Axin1.
USP5 leads to the deubiquitination of HDAC2. 1 / 1
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Moreover, USP5 interacted with HDAC2, and disruption of USP5 enhanced the ubiquitination of HDAC2.
USP5 deubiquitinates WT1. 1 / 1
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We further identified that USP5 deubiquitinated WT1 and stabilized its expression.
USP5 deubiquitinates FOXM1. 1 / 1
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USP5 deubiquitinates MAFB. 1 / 1
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USP5 was found to interact with c-Maf and prevented it from degradation by decreasing its polyubiquitination level| Notably, MafA and MafB are also members of the c-Maf family, however, USP5 failed to deubiquitinate MafA, suggesting its substrate specificity.
USP5 desumoylates USP5. 1 / 1
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We acknowledge the caveat that a USP5 construct with a point mutation that prevents SUMOylation is not strictly equivalent to deSUMOylation of USP5.

Other Statements

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Nitric oxide affects USP5
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Nitric oxide inhibits USP5.
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NO inhibits isopeptidase T activity in a concentration dependent manner.

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Furthermore, it is possible that NO may prevent protein breakdown by affecting the activity of isopeptidase T through S nitrosylation of active site cysteines.

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We show, for the first time, that NO inhibits isopeptidase T activity in the vasculature, most likely by S nitrosylation of a critical cysteine residue, a common mechanism by which NO regulates the activity of cysteine proteases.

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To determine if NO inhibits isopeptidase T activity via modification of cysteine thiol groups, DTT (5 mmol/L) was added to the activity assay before SNAP (1000 mumol/L).

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This correlation between the effect of NO on isopeptidase T activity and the presence of S nitrosylated isopeptidase T is further strengthened by evidence that NO inhibits isopeptidase T activity in a concentration dependent fashion in vitro.

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As NO can cause S nitrosylation of active-site cysteines, we hypothesize that NO inhibits isopeptidase T activity through S nitrosylation.

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NO inhibited recombinant isopeptidase T activity by 82.8% (t = 60 minutes, P <.001 vs control).

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We demonstrate here that NO inhibits the activity, but not levels, of isopeptidase T in VSMC in vitro, while decreasing its levels and increasing ubiquitinated proteins in the vasculature in vivo.

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We expect that these experiments would indicate that NO decreases isopeptidase T activity in vivo, which would lead to ubiquitin-proteasome pathway inhibition as a result of accumulation of proteins with unprocessed K48 linked polyubiquitin chains.

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Dithiothreitol and glutathione (5 mmol/L) both significantly reversed NO mediated inhibition of isopeptidase T activity (P <.001).
Nitric oxide decreases the amount of USP5.
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Nitric oxide decreases the amount of USP5. 4 / 5
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Although NO decreased the overall levels of isopeptidase T throughout the arterial wall at both time points after injury, the most prominent decrease was seen at 14 days.

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We provide evidence that, although administration of NO in vitro had no effect on isopeptidase T levels or intracellular localization in VSMC, external administration of NO in vivo in a carotid artery model of neointimal hyperplasia decreased isopeptidase T levels, while increasing levels of ubiquitinated proteins.

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Finally, we show that periadventitial administration of NO decreases levels of isopeptidase T in an animal model of neointimal hyperplasia, which correlates with increased ubiquitinated protein levels.

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Isopeptidase T was located mostly in the cytoplasm (XREF_FIG), and addition of NO did not affect intracellular localization of isopeptidase T. NO decreases isopeptidase T levels in vivo.
Nitric oxide increases the amount of USP5.
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Nitric oxide increases the amount of USP5. 3 / 4
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Local administration of NO may prevent neointimal hyperplasia by inhibiting isopeptidase T levels and activity in the vasculature, thereby inhibiting the 26S proteasome in VSMCs.

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Nitric oxide may inhibit neointimal hyperplasia by decreasing isopeptidase T levels and activity in the vasculature.

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NO caused a time dependent increase in S nitrosylated isopeptidase T levels in VSMCs, which was reversible with dithiothreitol, indicating that isopeptidase T undergoes reversible S nitrosylation on exposure to NO in vitro.
Nitric oxide activates USP5.
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NO causes S nitrosylation of isopeptidase T in a time dependent manner.

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We conclude that local administration of NO may prevent the formation of neointimal hyperplasia by inhibiting isopeptidase T activity via S nitrosylation, resulting in accumulation of unanchored polyubiquitin chains and further inhibiting the 26S proteasome.

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Local administration of NO may prevent neointimal hyperplasia by targeting isopeptidase T and inhibiting the 26S proteasome.
Mebendazole affects USP5
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Mebendazole inhibits USP5.
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Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf , thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation .

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Mebendazole inhibits the USP5 and c-Maf axis and induces c-Maf degradation via the ubiquitin-proteasome pathway.

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From this screen, we identified mebendazole, an agent widely used for the treatment of human gastrointestinal parasitic infections [9], selectively induces MM cell apoptosis by targeting USP5 and c-Maf signaling.Cell culture Human embryonic kidney cells (HEK293T) were maintained in Dulbecco 's modified Eagle 's medium.

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In the above studies , mebendazole was demonstrated to downregulate USP5 expression and disrupt the interaction between USP5 and c-Maf .

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The above studies provided strong evidence that mebendazole inhibits the USP5 and c-Maf axis and induces MM cell apoptosis.

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The above results demonstrated that mebendazole suppressed the USP5 and c-Maf axis and promoted c-Maf degradation; therefore, mebendazole might downregulate the transcriptional activity of c-Maf.

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The results showed that mebendazole decreased the USP5 content in the c-Maf immunoprecipitates in both exogenous and endogenous contexts, as shown in HEK293T and MM cells, respectively, suggesting that the interaction between USP5 and c-Maf was disrupted by mebendazole.

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Collectively, these results thus showed marked synergy between mebendazole and USP5 inhibitors or anti-MM drugs such as daunorubicin.Mebendazole delays the growth of human multiple myeloma xenografts in a nude mouse model The above studies provided strong evidence that mebendazole inhibits the USP5 and c-Maf axis and induces MM cell apoptosis.

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From this screen, we identified mebendazole, an agent widely used for the treatment of human gastrointestinal parasitic infections [XREF_BIBR], selectively induces MM cell apoptosis by targeting USP5 and c-Maf signaling.

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Mebendazole elicits potent antimyeloma activity by inhibiting the USP5 and c-Maf axis.
Mebendazole decreases the amount of USP5.
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Mebendazole decreases the amount of USP5. 8 / 8
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Notably, we found that USP5 mRNA expression was also decreased by mebendazole, suggesting that mebendazole might suppress USP5 transcription.

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Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf, thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation.

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The mechanistic investigation showed that mebendazole not only prevents the interaction between USP5 and c-Maf but also suppresses USP5 transcription, thus inducing c-Maf proteasomal degradation.

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In the above studies, mebendazole was demonstrated to downregulate USP5 expression and disrupt the interaction between USP5 and c-Maf.

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The mechanistic investigation showed that mebendazole not only prevents the interaction between USP5 and c-Maf but also suppresses USP5 transcription, thus inducing c-Maf proteasomal degradation.Notably, mebendazole is cytotoxic to various cancer cells, including MM and leukemia cells, at higher concentrations (data not shown); however, it elicits selective anti-MM activity at low concentrations.

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Notably, we found that USP5 mRNA expression was also decreased by mebendazole, suggesting that mebendazole might suppress USP5 transcription.Because c-Maf turnover is processed via the proteasome, we sought to determine whether mebendazole induced c-Maf Fig. 2 Mebendazole inhibits USP5 expression and induces c-Maf degradation via the ubiquitin-proteasome pathway.

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The results showed that mebendazole downregulated the protein expression of both USP5 and c-Maf in both LP1 and RPMI-8226 cells.

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The results showed that mebendazole downregulated the protein expression of both USP5 Fig. 1 Identification of mebendazole as a promoter of c-Maf protein degradation.
Mebendazole activates USP5.
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HEK293T cells cotransfected with MARE.luci, c-Maf, and USP5 were treated with mebendazole for 24h, followed by a luciferase assay.

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These data indicated that USP5 effectively promoted EMT in NSCLC cells.

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Knockdown of USP5 inhibits SLUG deubiquitination and inhibits HCC cells proliferation, metastasis, and invasion, while overexpression of USP5 promotes SLUG stability and EMT in vitro and in vivo.

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USP5 targets the transcription factor SLUG and then induces EMT in hepatocellular carcinoma cells ( Meng et al ., 2019 ) .

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These data indicated that USP5 promotes NSCLC metastasis by inducing EMT.

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In previous study, USP5 was found promoting EMT by stabilizing SLUG in hepatocellular carcinoma XREF_BIBR.

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USP5 induces EMT and promotes migration and invasion in NSCLC cells .

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USP5 promotes EMT and metastasis in hepatocellular carcinoma.

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USP5 promotes EMT and the invasion and migration of NSCLC cells .

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USP5 promotes EMT through the regulation of GSK-3beta / beta-catenin .

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USP5 enhanced epithelial-mesenchymal transition (EMT)-induced metastasis by stabilizing SLUG.
USP5 increases the amount of epithelial to mesenchymal transition.
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Furthermore, USP5 overexpression significantly enhanced, whereas USP5 silencing significantly decreased the expression of EMT proteins and migration and invasion of NSCLC cells.
Ubiquitin affects USP5
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Ubiquitin inhibits USP5.
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In addition, ubiquitin binds to and inhibits USP5.

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Also, USP5 has an asparagine at the corresponding position and is inhibited by ubiquitin.

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In addition , ubiquitin binds to and inhibits USP5 .

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Also, USP5 has an asparagine at the corresponding position and is inhibited by ubiquitin.

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In addition, ubiquitin binds to and inhibits USP5.

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Also , USP5 has an asparagine at the corresponding position and is inhibited by ubiquitin .

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Kinetic studies on the inhibition of isopeptidase T by ubiquitin aldehyde.

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In contrast, Ub activated IPaseT is inhibited by Ub-H through a three-step process.

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In addition, ubiquitin binds to and inhibits USP5.
Ubiquitin-G76A inhibits USP5. 1 / 1
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As expected, Ub G76A -Ub did not label or inhibit OTULIN and USP5, but it also induced the dose dependent assembly of Ub chains that could be detected with anti-M1-polyUb antibody (XREF_FIG G).
Ubiquitin activates USP5.
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Both free and substrate conjugated polyubiquitin chains accumulate in leon mutants, suggesting that abnormal ubiquitin homeostasis caused tissue disorder and lethality in leon mutants.

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Recognition of the free C-terminus of the proximal ubiquitin in a poly-ubiquitin chain has been shown to stimulate the activity of USP5.

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Our finding suggests that the previous finding that ubiquitin (not C-terminal truncated) enhances the activity of USP5 37 is due to the binding of the beta-grasp domain of ubiquitin.

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It is known that occupancy of the S1 ' site by the proximal ubiquitin activates USP5 and that the C-terminal glycine (G76) of this ubiquitin is determinant for this activation XREF_BIBR XREF_BIBR.

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While submicromolar concentrations of ubiquitin activate isopeptidase T, higher concentrations are inhibitory.
USP5 affects TP53
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USP5 inhibits TP53.
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USP5 inhibits TP53. 8 / 9
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Suppression of the human USP5 gene also causes the accumulation of unanchored polyubiquitins and enhances the intracellular level of p53 [XREF_BIBR].

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Activation of p53 can be accounted for by the ability of USP5 suppression to inhibit the proteasomal degradation of p53 without affecting the degradation of Mdm2.

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Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53.

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Usp5 KD consistently led to p53 induction and accumulation of ubiquitinated p53 adducts while Usp5 overexpression diminished p53 content.

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XREF_BIBR, XREF_BIBR Further, Dayal et al reported that isopeptidase T inhibition causes both p53 activation and unanchored polyubiquitin chain accumulation.

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Previous study has shown that Usp5 knockdown promoted p53 activation, so we suppose that Usp5 may be involved in carcinogenesis.

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Similarly, the COPS2, COPS3, and USP5 which may degrade p53 were significantly upregulated in OCHA L compared to OTCS H (XREF_TABLE).

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Recently, it has been shown that Usp5 knockdown induces p53 activation [XREF_BIBR], and Usp5 controls activation of apoptotic signaling as well as Jun N-Terminal kinase pathway during eye development [XREF_BIBR].
USP5 activates TP53.
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USP5 activates TP53. 6 / 8
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Knockdown of the mammalian IsoT (USP5) causes a similar accumulation of polyubiquitin as well as an increase in the proteasomal substrate p53 [XREF_BIBR].

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It has recently been shown that knock-down of the deubiquitinating enzyme USP5 (isopeptidaseT) causes p53 activation XREF_BIBR.

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Usp5 KD resulted in up-regulation of p53 in w/t p53 A375 cells and up-regulation of p73 in p53 mutant SK-Mel28 cells, suggesting that both proteins can be modulated by Usp5.

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Depletion of USP5 has been reported to cause accumulation of nuclear p53 and increase p53 transcriptional activity.

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Intriguingly, USP5 has been confirmed to mediate p53 signaling XREF_BIBR, wnt-beta-catenin pathway XREF_BIBR, Type I interferon signaling pathway XREF_BIBR, Notch and RTK signaling pathway XREF_BIBR.

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In previous study, p53 stabilization was mediated by Usp5 through accumulation of unanchored poly-ubiquitin chains which competed with p53 for entering into the proteasome [XREF_BIBR].
USP5 decreases the amount of TP53.
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USP5 decreases the amount of TP53. 1 / 1
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Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway.
Modified USP5 decreases the amount of TP53. 1 / 1
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Conversely, Usp5 overexpression suppressed the expression of p14 ARF and p53 and promoted Mdm2 expression, leading to inactivation of this signaling.
USP5 increases the amount of TP53.
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USP5 increases the amount of TP53. 1 / 1
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We used Usp5 knockdown (KD), overexpression and enzyme inhibition to demonstrate that Usp5 suppresses p53 and FAS levels in melanoma and is associated with loss of checkpoint control and apoptotic sensitivity to kinase inhibitors and other agents.

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It has been reported that USP5 promotes tumor proliferation and tumorigenesis through the deubiquitination of histone deacetylase 2 (HDAC2) and beta-catenin.

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The siRNA induced knockdown of Usp5 inhibited cell proliferation, migration ability and drug resistance.

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Furthermore, the colony formation assays also showed that USP5 knockdown inhibited proliferation of PANC-1 and SW1990, two PDAC cell lines.To further evaluate the role of USP5 in PDAC progression, six[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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We concluded that USP5 promoted the proliferation of trophoblast cells via the up-regulation of the Wnt and beta-catenin signaling pathway.

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Taken together, these results suggested that USP5 could evidently promote pancreatic cancer cells proliferation and metastasis.

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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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CCK-8 assay and colony formation experiments showed that overexpression of USP5 in Panc1 cells dramatically increased the proliferation.

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Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5 and c-Maf axis could be a potential target for myeloma therapy.

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USP5 was recently found to stabilize c-Maf protein and promote myeloma cell proliferation and survival XREF_BIBR.

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Disruption of USP5 profoundly repressed cell proliferation by inducing cell cycle G0/G1 phase arrest in ovarian cancer cells.

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The siRNA-induced knockdown of Usp5 inhibited cell proliferation, migration ability and drug resistance.
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Second, loss of usp5 activates apoptosis and the JNK pathway.

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Loss of usp5 activates apoptosis and the JNK pathway.

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USP5 knockdown leads to DNA damage, cell cycle arrest and apoptosis in PDAC cells.

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USP5 deficiency also induces DNA damage , cell cycle arrest and apoptosis in pancreatic ductal adenocarcinoma cells ( 51 , 53 ) .

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Usp5 knockdown suppressed cell viability and induced apoptosis in HCC cells.

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Moreover, inhibiting USP5 by genetic shRNA or small molecule inhibitors such as WP1130 leads to MM cell apoptosis [XREF_BIBR].

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In the present study , our objective is to study in broad the secondary down-stream effect after depleting USP5 or USP8 , which were initially showed to induce apoptosis in various cancers .

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Our study showed that Usp5 knockdown induced cell cycle arrest and apoptosis, at least partially associated with p53 expression.

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Moreover, inhibiting USP5 by genetic shRNA or small molecule inhibitors such as WP1130 leads to MM cell apoptosis [8].

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Therefore, usp5 suppression of apoptosis is necessary for the differentiation of photoreceptors.
USP5 activates apoptotic process.
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Further functional investigation also showed that Usp5 knockdown suppressed cell proliferation, migration, drug resistance and induced apoptosis; on the other hand, Usp5 overexpression promoted colony formation, migration, drug resistance and tumorigenesis.

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In the present study, our objective is to study in broad the secondary down-stream effect after depleting USP5 or USP8, which were initially showed to induce apoptosis in various cancers.

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In both w/t and mutant p53 expressing cells, Usp5 KD enhanced the onset or extent of apoptosis induced by vemurafenib, with evidence for activation of both the intrinsic and extrinsic pathway.

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USP5 deficiency also induces DNA damage, cell cycle arrest and apoptosis in pancreatic ductal adenocarcinoma cells.

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To focus on the mechanisms by which USP5 regulates eye development, we first wanted to know whether apoptosis is induced by the knock-out of usp5, since there is a possibility that interference with the differentiation process leads to apoptosis.
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USP5 Promotes Metastasis in Non-Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition .

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USP5 Promotes Metastasis in Non Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition

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USP5 knockdown inhibits the progression and metastasis of pancreatic cancer.

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USP5 Promotes Metastasis in Non-Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition via Wnt / beta-Catenin Pathway Ubiquitin-specific protease 5 ( USP5 ) is a deubiquitinating enzyme that functions as an oncoprotein in a variety of human cancers .

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USP5 Promotes Metastasis in Non Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition via Wnt and beta-Catenin Pathway.

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USP5 overexpression promotes the progression and metastasis of pancreatic cancer.

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USP5 promotes EMT and metastasis in hepatocellular carcinoma.

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Results elucidated that USP5 contribute to cell invasion and metastasis in pancreatic cancer.

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All the results indicated that USP5 promotes the growth and metastasis of hepatocellular carcinoma.

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Taken together, these results suggested that USP5 could evidently promote pancreatic cancer cells proliferation and metastasis.
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Moreover, USP5 intervention by shRNA knockdown has been reported to prevent the metastasis of hepatocellular carcinoma in vivo.
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In contrast with USP5 overexpression, knockdown USP5 inhibited cell invasion and migration.

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Meanwhile, USP5 was found to promote EMT, invasion, and migration of NSCLC cells, and its expression is correlated with EMT and metastasis in NSCLC tissues.

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Transwell assay and wound healing assay results also showed that knockdown of USP5 inhibited cell invasion and migration and overexpression of USP5 promoted cell invasion and migration.

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Here , we found that USP5 resulted in an increase in E-cadherin expression and decreases in N-cadherin and vimentin expression , inhibiting invasion and migration in NSCLC cells .

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It was suggested that USP5 promoted EMT , invasion , and migration in NSCLC cells .

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USP5 promotes EMT and the invasion and migration of NSCLC cells.

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Here, we found that USP5 resulted in an increase in E-cadherin expression and decreases in N-cadherin and vimentin expression, inhibiting invasion and migration in NSCLC cells.

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Results elucidated that USP5 contribute to cell invasion and metastasis in pancreatic cancer.

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Meanwhile , USP5 was found to promote EMT , invasion , and migration of NSCLC cells , and its expression is correlated with EMT and metastasis in NSCLC tissues .

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It was suggested that USP5 promoted EMT, invasion, and migration in NSCLC cells.
USP5 is modified
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USP5 is desumoylated.
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USP5 is desumoylated. 9 / 9
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AMSH, associated molecule with the SH3 domain of STAM; AMSHLP, AMSH-like protease; ATXN3, ataxin 3; BAP1, BRCA1-associated protein 1; CEZANNE, cellular zinc finger anti-NF-κB protein; CSN, COP9 signalosome complex subunit; CYLD, cylindromatosis; DESI, desumoylating isopeptidase; EIF3, eukaryotic translation initiation factor 3; JAMM, JAB1, MPN, MOV34 family; JOSD, josephin domain; MINDY, motif-interacting with ubiquitin-containing novel DUB family; MJD, Machado–Josephin domain-containing protease; OTUD, OTU domain-containing protein; PRPF8, pre-mRNA-processing splicing factor 8; UCHL, ubiquitin carboxy-terminal hydrolase-like; USP, ubiquitin-specific protease; VCPIP1, valosin-containing protein p97/p47 complex-interacting protein 1.

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DeSUMOylating isopeptidase: a second class of SUMO protease.

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Moreover, two additional SUMO isopeptidases have been described in humans, deSUMOylating isopeptidase (DeSI), and the ubiquitin-specific protease-like 1 (USPL1) ( xref ) [ xref ].

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In addition to the SENP family, de-SUMOylating isopeptidase 1 and 2 (DeSI1 and 2) and ubiquitin-specific protease-like 1 (USPL1) can also function as SUMO-protease.

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We acknowledge the caveat that a USP5 construct with a point mutation that prevents SUMOylation is not strictly equivalent to deSUMOylation of USP5.

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Other SUMO proteases, such as Ubiquitin‐Specific Peptidase‐Like protein 1 xref , DeSumoylating Isopeptidase 1 and DeSumoylating Isopeptidase 2 xref , have been identified but do not appear to be involved in changing global SUMOylation patterns.

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Recently, several additional SUMO proteases have been identified, DeSumoylating Isopeptidase 1 and 2 (DeSI1 and DeSI2; Shin et al., xref ) and USPL1 (Ubiquitin-Specific Protease-Like 1; Schulz et al., xref ).

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Hence, preventing deSUMOylation of USP5 could provide a strategy for enhancing USP5 interactions with Cav3.2, which would in turn be predicted to lead to analgesia.

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Members of the second family of SUMO proteases are desumoylating isopeptidase (DeSI) 1 and 2, which are primarily used for deconjugation of SUMO (reviewed in refs. xref , xref , xref ).
USP5 is deubiquitinated.
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USP5 is deubiquitinated. 1 / 1
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Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1.
USP5 affects STAT3
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USP5 activates STAT3.
| 1 7
USP5 activates STAT3. 8 / 8
| 1 7

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USP5 mediates STAT3 signaling in pancreatic cancer.

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Inhibition of deubiquitinase USP5 suppresses STAT3 signaling and attenuates the inflammatory response of chronic periodontitis.

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Suppressing USP5 inhibited STAT3 signaling in PDLSCs .

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In contrast, knockdown of USP5 suppressed the activation of STAT3.

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In this study, we confirmed that USP5 mediated STAT3 signaling.

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High USP5 expression promotes both progression and metastasis by activating STAT3 signaling.

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USP5 was also proved to mediate STAT3 signaling in pancreatic cancer cells.

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Suppressing USP5 inhibited STAT3 signaling in PDLSCs.
USP5 inhibits STAT3.
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USP5 inhibits STAT3. 1 / 1
| 1

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Suppression deubiquitinase USP5 inhibits the inflammatory response of chronic periodontitis by suppressing STAT3 signaling.
USP5 decreases the amount of STAT3.
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USP5 decreases the amount of STAT3. 1 / 1
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The DUB inhibitor described here reduced Usp9x and Usp5 activity, induced p53, FAS and NOXA, reduced pStat3 levels and amplified vemurafenib apoptotic activity in vitro.
USP5 affects SNAI2
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USP5 activates SNAI2.
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USP5 activates SNAI2. 7 / 7
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USP5 promotes epithelial-mesenchymal transition by stabilizing SLUG in hepatocellular carcinoma.

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Consistently, USP5 overexpression prolonged the half-life of SLUG.

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Knockdown of USP5 inhibits SLUG deubiquitination and inhibits HCC cells proliferation, metastasis, and invasion, while overexpression of USP5 promotes SLUG stability and EMT in vitro and in vivo.

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In previous study, USP5 was found promoting EMT by stabilizing SLUG in hepatocellular carcinoma XREF_BIBR.

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USP5 targets the transcription factor SLUG and then induces EMT in hepatocellular carcinoma cells.

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ChIP analysis showed that knockdown of USP5 decreased the binding of SLUG to the promoter of E-cadherin.

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However, the importance of USP5 promoted SLUG stabilization in EMT must be examined.
USP5 inhibits SNAI2.
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USP5 inhibits SNAI2. 2 / 2
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Luciferase reporter gene assay showed that knockdown USP5 interfered with the transcriptional inhibition of SLUG on E-cadherin, and over-expression of USP5 promoted the transcriptional inhibition of SLUG on E-cadherin.

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CHX and in vivo deubiquitination assay revealed that USP5 removed ubiquitin on SLUG and prevented SLUG from being ubiquitin degraded.
USP5 increases the amount of SNAI2.
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Modified USP5 increases the amount of SNAI2. 1 / 1
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USP5 overexpression increased SLUG expression in PLC-PRF-5 and Hep3B cells.
USP5 affects MAF
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USP5 activates MAF.
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USP5 activates MAF. 6 / 6
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In the functional studies, USP5 was found to promoted the transcriptional activity of c-Maf.

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In myeloma cells , USP5 stabilizes the c-Maf transcription factor , where inhibition of USP5 promotes c-Maf degradation and leads to apoptosis in myeloma cells [ 15 ] .

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In myeloma cells, USP5 stabilizes the c-Maf transcription factor, where inhibition of USP5 promotes c-Maf degradation and leads to apoptosis in myeloma cells [XREF_BIBR].

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Ectopic expression of USP5 significantly increased the transcriptional activity of c-Maf in terms of the measured luciferase activity.

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In contrast , knockdown of USP5 leads to c-Maf degradation and MM cell apoptosis [ 8] .

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Notably, we found that USP5 mRNA expression was also decreased by mebendazole, suggesting that mebendazole might suppress USP5 transcription.Because c-Maf turnover is processed via the proteasome, we sought to determine whether mebendazole induced c-Maf Fig. 2 Mebendazole inhibits USP5 expression and induces c-Maf degradation via the ubiquitin-proteasome pathway.
USP5 inhibits MAF.
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USP5 inhibits MAF. 2 / 2
| 1 1

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C-Maf ubiquitination can be reversed by the deubiquitinase USP5 because USP5 prevents c-Maf from polyubiquitination and degradation [8].

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C-Maf ubiquitination can be reversed by the deubiquitinase USP5 because USP5 prevents c-Maf from polyubiquitination and degradation [ 8] .
USP5 affects Ubiquitin
| 1 6
| 1 6

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Isopeptidase T specifically degrades unanchored polyubiquitin chains by removing individual ubiquitin subunits in a step-wise fashion from the proximal end of the chain (Hadari et al., 1992).

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Thus, Leon and USP5 holds Ubqn in check and prevents ubiquitin homeostatic imbalance, making USP5 as a potential candidate disease gene in ubiquitin homeostasis related diseases.

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Intriguingly, inhibition of ubiquitin by isopeptidase inhibitor (G5), which causes depletion of free nuclear ubiquitin [ xref ], prevented Top 1 degradation in CPT-treated T cells (4).

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Interestingly, although the RIG-I complex isolated from HEK293T cells contains both IsoT sensitive unanchored ubiquitin chains and IsoT resistant ubiquitin conjugates, the IsoT treatment completely abolished the ability of these ubiquitin chains to activate RIG-I (XREF_FIG), strongly suggesting that unanchored polyUb chains are responsible for RIG-I activation.

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We observed that both LRSAM1 and HRD1 displayed apparent autoubiquitination, and much of this signal was resistant to IsoT treatment, which degrades unanchored ubiquitin chains.

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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].

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IsoT also reduced the pro-IL-1beta-associated ubiquitin (XREF_FIG, 4 th lane).
SMURF1 affects USP5
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SMURF1 decreases the amount of USP5.
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SMURF1 decreases the amount of USP5. 2 / 3
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Moreover, down-regulation of USP5 expression by Smurf1 was presented in a dose dependent manner.

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In this study, we identified the HECT-type E3 ligase, Smurf1, could regulate the stability and function of USP5.First of all, we demonstrated that USP5 protein levels could be reduced by Smurf1 in a d[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
SMURF1 inhibits USP5.
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SMURF1 inhibits USP5. 2 / 2
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Taken together, our results demonstrated that Smurf1 could promote USP5 degradation through increasing USP5 ubiquitination.Tumor necrosis factor alpha (TNF-alpha) is a central mediator of the inflamma[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Because the ubiquitin ligase activity of Smurf1 was required for down-regulation of USP5 protein levels, we next sought to determine whether USP5 degradation mediated by Smurf1 is a consequence of ubi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
SMURF1 bound to USP5 inhibits USP5. 1 / 1
| 1

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Smurf1 interacted with USP5 and mediated the ubiquitination and proteasomal degradation of USP5.
SMURF1 increases the amount of USP5.
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SMURF1 increases the amount of USP5. 1 / 1
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Moreover, down-regulation of USP5 expression by Smurf1 was presented in a dose dependent manner.
USP5 affects FOXM1
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USP5 activates FOXM1.
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USP5 activates FOXM1. 2 / 3
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USP5 promotes tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein.

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To investigate whether USP5 prolonged the half-life of FoxM1, we transfected PANC-1 cells with USP5 and measured FoxM1 expression level in the presence of the translational inhibitor CHX.
USP5 increases the amount of FOXM1.
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USP5 increases the amount of FOXM1. 1 / 1
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As expected, knockdown of USP5 in PANC-1 cells decreased FoxM1 protein level but did not affect FoxM1 mRNA level.
Modified USP5 increases the amount of FOXM1. 1 / 1
| 1

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Overexpression of USP5 reduces the endogenous ubiquitination of FoxM1 and increases FoxM1 expression [25].
USP5 decreases the amount of FOXM1.
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USP5 decreases the amount of FOXM1. 1 / 1
| 1

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Knockdown of USP5 in PANC-1 cells decreased FoxM1 protein level but did not affect FoxM1 mRNA level, indicating that FoxM1 was regulated at the post-transcriptional level.
Modified USP5 decreases the amount of FOXM1. 1 / 1
| 1

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Overexpression of USP5 reduces the endogenous ubiquitination of FoxM1 and increases FoxM1 expression [25].
USP5 affects cell cycle
| 1 5
USP5 activates cell cycle.
| 1 4
| 1 4

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USP5 deficiency also induces DNA damage, cell cycle arrest and apoptosis in pancreatic ductal adenocarcinoma cells.

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Disruption of USP5 profoundly repressed cell proliferation by inducing cell cycle G0/G1 phase arrest in ovarian cancer cells.

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It has identified NQQ1 as a potential drug target for host directed tuberculosis therapy, ATP1A1 as a gene that regulates aurilide B cytotoxicity, and the deubiquitinating enzyme, USP5, which modulates cell cycle regulators.34, 35, 36 The shRNA screening system has also identified HIF1alpha as a TERT regulator using mouse ES cells.37 In this study in a HCC cell line, we identified two genes, C15orf55 and C7orf43, as activators of TERT transcription through SP1 and YAP1, respectively.

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USP5 deficiency also induces DNA damage , cell cycle arrest and apoptosis in pancreatic ductal adenocarcinoma cells ( 51 , 53 ) .

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It is noteworthy that USP5 is highly expressed in Gliomas [XREF_BIBR], where p53 stabilization effect caused due to the accumulation of unanchored polyubiquitin in the absence of USP5 causes cell cycle arrest [XREF_BIBR].
USP5 inhibits cell cycle.
| 1
| 1

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Our study showed that Usp5 knockdown induced cell cycle arrest and apoptosis, at least partially associated with p53 expression.
Formononetin affects USP5
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Formononetin activates USP5.
| 3
| 3

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All the results showed that Formononetin directly targets USP5.

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To explore the influence of Formononetin on USP5 and SLUG axis, PLC-PRF-5 cells treated with Formononetin at different concentrations were used for WB analysis.

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In this study, we show that Formononetin directly targets USP5 and inhibits its deubiquitinase activity, thereby destabilizing SLUG and repressing EMT and HCC progression.
Formononetin inhibits USP5.
| 2
| 2

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Small molecules inhibitor WP1130 XREF_BIBR and Chinese medicine Formononetin XREF_BIBR were reported to inhibit USP5, which further indicated that targeting USP5 might be an effective strategy in pancreatic cancer treatment.

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To investigate the influence of Formononetin on inhibiting USP5, ChIP assay was conducted in cells treated with Formononetin at different concentrations.
USP5 affects IFNB1
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USP5 inhibits IFNB1.
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USP5 inhibits IFNB1. 3 / 3
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In addition , a recent systematic functional screening assay revealed that USP5 inhibits IFNb expression and promotes VSV replication by recruiting STIP1 homology and Ubox containing protein 1 ( STUB1 ) to degrade RIG-I ( 40 ) .

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Moreover , USP5 suppresses IFN-beta expression and enhances VSV replication by recruiting STUB1 to degrade RIG-I ( 40 ) .

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Moreover , USP5 suppresses IFNb expression and enhances VSV replication by recruiting STUB1 to degrade RIG-I ( 40 ) .
USP5 decreases the amount of IFNB1.
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USP5 decreases the amount of IFNB1. 1 / 1
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Moreover, USP5 suppresses IFN-β expression and enhances VSV replication by recruiting STUB1 to degrade RIG-I (40).
USP5 activates IFNB1.
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USP5 activates IFNB1. 1 / 1
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In contrast, USP5 which shares 80% sequence similarity with USP13, neither interacted with STING in an overexpression system nor inhibited cGAS and STING induced activation of IFN-beta promoter in reporter assays (XREF_FIG), indicating a specific interaction between USP13 and STING.
USP5 affects Interferon
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USP5 inhibits Interferon.
| 1 1
| 1 1

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Type I IFN plays an important role in antiviral infection process , and USP5 can inhibit the production of type I IFN .

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Type I IFN plays an important role in antiviral infection process, and USP5 can inhibit the production of type I IFN.
USP5 increases the amount of Interferon.
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USP5 increases the amount of Interferon. 1 / 1
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In summary, this study reveals that USP5 is able to activate higher levels of interferon by increasing RIG-I protein levels, and thus implement antivirus functions.
USP5 decreases the amount of Interferon.
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USP5 decreases the amount of Interferon. 1 / 1
| 1

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In addition, a recent systematic functional screening assay revealed that USP5 inhibits IFNβ expression and promotes VSV replication by recruiting STIP1 homology and U-box containing protein 1 (STUB1) to degrade RIG-I (40).
USP5 activates Interferon.
| 1
| 1

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In summary , this study reveals that USP5 is able to activate higher levels of interferon by increasing RIG-I protein levels , and thus implement antivirus functions .
USP5 affects DDX58
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USP5 increases the amount of DDX58.
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USP5 increases the amount of DDX58. 2 / 2
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USP5 was also able to enhance the expression of RIG-I and activate higher levels of IFNphi1 stimulated by Poly (I : C).

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In summary, this study reveals that USP5 is able to activate higher levels of interferon by increasing RIG-I protein levels, and thus implement antivirus functions.
USP5 inhibits DDX58.
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USP5 inhibits DDX58. 1 / 1
| 1

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IsoT somewhat reduces the MAVS stimulatory activity of RIG-I ( sample 2 ) , but is still more efficient than RIG-I without RIPLET ( sample 3 ) .
USP5 bound to STUB1 inhibits DDX58. 1 / 1
| 1

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A systematic functional screening revealed that USP5 can interact with and recruit STUB1 to mediate the degradation of RIG-I, thus enhancing VSV replication.
USP5 activates DDX58.
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USP5 activates DDX58. 1 / 1
| 1

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USP5 was also able to enhance the expression of RIG-I and activate higher levels of IFNphi1 stimulated by Poly ( I : C ) .
USP5 affects mebendazole
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USP5 increases the amount of mebendazole. 4 / 4
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Notably, we found that USP5 mRNA expression was also decreased by mebendazole, suggesting that mebendazole might suppress USP5 transcription.

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The mechanistic investigation showed that mebendazole not only prevents the interaction between USP5 and c-Maf but also suppresses USP5 transcription, thus inducing c-Maf proteasomal degradation.

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The mechanistic investigation showed that mebendazole not only prevents the interaction between USP5 and c-Maf but also suppresses USP5 transcription, thus inducing c-Maf proteasomal degradation.Notably, mebendazole is cytotoxic to various cancer cells, including MM and leukemia cells, at higher concentrations (data not shown); however, it elicits selective anti-MM activity at low concentrations.

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Notably, we found that USP5 mRNA expression was also decreased by mebendazole, suggesting that mebendazole might suppress USP5 transcription.Because c-Maf turnover is processed via the proteasome, we sought to determine whether mebendazole induced c-Maf Fig. 2 Mebendazole inhibits USP5 expression and induces c-Maf degradation via the ubiquitin-proteasome pathway.
USP5 affects cell growth
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USP5 activates cell growth.
| 3
| 3

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While USP5 knockdown effectively inhibited CRC cell growth, overexpressed USP5 promoted the growth of CRC cells and made them more resistant to doxorubicin (DOX).

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Usp5 overexpression promoted cell growth in vitro and stimulated tumorigenicity in vivo.

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In Pancreatic cancer, USP5 was shown to encourage oncogenicity by modulating the cell cycle regulators, as inhibition of USP5 attenuated pancreatic cell growth [XREF_BIBR].
USP5 inhibits cell growth.
| 1
| 1

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The forced expression of USP5 isoform 1 in two GBM cell lines inhibited cell growth and migration, implying an important role for USP5 splicing in gliomagenesis.
USP5 affects CDKN2A
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USP5 inhibits CDKN2A.
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USP5 inhibits CDKN2A. 3 / 3
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The P14 ARF -P53 signaling was activated by USP5 knockdown in HCC cells.

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Our results showed that the p14 ARF -p53 signaling was activated by Usp5 knockdown in HCC cells.

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Usp5 knockdown induced the activation of p14 ARF -p53 signaling in HCC cells.
USP5 decreases the amount of CDKN2A.
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Modified USP5 decreases the amount of CDKN2A. 1 / 1
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Conversely, Usp5 overexpression suppressed the expression of p14 ARF and p53 and promoted Mdm2 expression, leading to inactivation of this signaling.
USP5 affects CACNA1H
| 4
USP5 increases the amount of CACNA1H.
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USP5 increases the amount of CACNA1H. 2 / 2
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Knockdown of USP5 via shRNA or preventing its association with the channel by using Tat epitope fused disruptor peptides decreased Cav3.2 protein levels and produced analgesia in models of inflammatory and neuropathic pain in mice.

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Knockdown of USP5 via shRNA increases Cav3.2 ubiquitination, decreases Cav3.2 protein levels, and reduces Cav3.2 whole-cell currents.
USP5 activates CACNA1H.
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USP5 activates CACNA1H. 2 / 2
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In the present study, we test the hypothesis that IL-1β activity can trigger USP5-mediated Cav3.2 channel plasticity to induce pain.

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The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3.2 channel activity.
SNAP25 affects USP5
| 4
SNAP25 inhibits USP5.
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SNAP25 inhibits USP5. 3 / 3
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A kinetics assay showed that isopeptidase T activity plateaued after 60 minutes, and SNAP concentrations above 250 mumol/L significantly inhibited isopeptidase T activity (XREF_FIG).

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Increasing concentrations of SNAP led to significantly increased inhibition of isopeptidase T activity (P <.001 at SNAP> = 500 mumol/L) (XREF_FIG).

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DTT significantly prevented SNAP mediated inhibition of isopeptidase T activity, restoring activity to 77.8% of control (* P <.001 vs control; ** P <.001 vs SNAP) (XREF_FIG).
SNAP25 activates USP5.
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SNAP25 activates USP5. 1 / 1
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GSH significantly prevented inhibition of isopeptidase T activity mediated by SNAP, with activity levels observed at 77.8% of control (* P <.001 vs control; ** P <.001 vs SNAP) (XREF_FIG).
USP5 affects FAS
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USP5 decreases the amount of FAS.
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USP5 decreases the amount of FAS. 2 / 2
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Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway.

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We used Usp5 knockdown (KD), overexpression and enzyme inhibition to demonstrate that Usp5 suppresses p53 and FAS levels in melanoma and is associated with loss of checkpoint control and apoptotic sensitivity to kinase inhibitors and other agents.
USP5 inhibits FAS.
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USP5 inhibits FAS. 1 / 1
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FAS reduction by Usp5 appears to be mediated at the transcriptional level, possibly through down-regulation of p53 and other factors (XREF_SUPPLEMENTARY).
USP5 increases the amount of FAS.
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USP5 increases the amount of FAS. 1 / 1
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In melanoma cells, USP5 has been reported to modulate FAS expression in a p53 dependent manner, thereby controlling growth [XREF_BIBR].
Glutathione affects USP5
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| 3

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GSH significantly prevented inhibition of isopeptidase T activity mediated by SNAP, with activity levels observed at 77.8% of control (* P <.001 vs control; ** P <.001 vs SNAP) (XREF_FIG).

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Dithiothreitol and glutathione (5 mmol/L) both significantly reversed NO mediated inhibition of isopeptidase T activity (P <.001).

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Dithiothreitol and glutathione prevent the inhibition of isopeptidase T activity by NO.
USP5 affects Pain
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USP5 activates Pain. 3 / 3
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This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the pain pathway.

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The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3.2 channel activity.

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We showed that depletion of USP5, or its uncoupling from Cav3.2 channels via delivery of Tat peptides prevented and/or reversed the pain phenotype in models of peripheral inflammation (i.e., formalin and CFA) and peripheral nerve injury (i.e., partial sciatic nerve ligation).
BRAF affects USP5
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BRAF activates USP5. 3 / 3
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Overall, our results demonstrate that BRAF activates Usp5 to suppress cell cycle checkpoint control and apoptosis by blocking p53 and FAS induction; all of which can be restored by small molecule-mediated Usp5 inhibition.

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Usp5 was consistently suppressed, but not fully inhibited, by kinase inhibitor or BRAF knockdown.

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Overall, our results demonstrate that BRAF activates Usp5 to suppress cell cycle checkpoint control and apoptosis by blocking p53 and FAS induction; all of which can be restored by small molecule mediated Usp5 inhibition.
Vemurafenib affects USP5
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Vemurafenib activates USP5.
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To determine whether BRAF mediated-DUB activation regulates the cellular response to vemurafenib, control and Usp5 KD cells were treated with vemurafenib for the interval indicated.

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To determine whether Usp5 KD (or G9) could overcome vemurafenib resistance, Usp5 KD A375R cells were left untreated or treated with vemurafenib (for 24 hrs) before assessing caspase activation, PARP and Bid cleavage.
Vemurafenib inhibits USP5.
| 1
| 1

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We compared DUB activity in vemurafenib and G9 treated cells and show that vemurafenib suppressed Usp5 activity in sensitive but not resistance cells, although pERK was reduced by kinase inhibitor in either cell type.
Doxycycline affects USP5
| 3
Doxycycline inhibits USP5.
| 2
| 2

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H2A.X in Western blot analyses in response to doxycycline induced USP5 knockdown.

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Cells were cultured for eleven days using the liquid overlay technique in the presence or absence of doxycycline to induce USP5 knockdown and cell viability repeatedly assessed by chemiluminescence assays.
Doxycycline activates USP5.
| 1
| 1

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Intriguingly, the cell cycle regulator p21 was also strongly and reproducibly upregulated in response to transient siRNA mediated USP5 knockdown, but this effect was reversed in stably transfected clones in which USP5 downregulation was mediated by doxycycline inducible shRNA constructs.
USP5 affects TNF
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USP5 activates TNF.
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USP5 activates TNF. 2 / 2
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Because inhibition of TNF-alpha production in RBL-2H3 cells treated with USP5 siRNA1 and USP5 siRNA2 was observed (XREF_FIG), we examined the effect of USP5 siRNA1 and USP5 siRNA2 on TNF-alpha mRNA expression.

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Taken together, our study for the first time clarified that the E3 ligase Smurf1 regulates USP5 protein stability and USP5 mediated TNF-alpha production through the ubiquitin proteasome pathway.
USP5 increases the amount of TNF.
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USP5 increases the amount of TNF. 1 / 1
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USP5, a stress granule protein, increases TNFα expression through the ubiquitin-proteasome pathway and regulates inflammatory response through Smurf1.
| PMC
USP5 affects Notch
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USP5 inhibits Notch.
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USP5 inhibits Notch. 2 / 2
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Loss of Usp5 results in upregulation of Notch signaling and downregulation of RTK signaling, leading to impaired photoreceptor development.

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The loss of the deubiquitinating protein Ubiquitin carboxyl-terminal hydrolase 5 (Usp5) leads to the upregulation of Notch during Drosophila melanogaster eye development [XREF_BIBR].
USP5 activates Notch.
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USP5 activates Notch. 1 / 1
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Intriguingly, USP5 has been confirmed to mediate p53 signaling XREF_BIBR, wnt-beta-catenin pathway XREF_BIBR, Type I interferon signaling pathway XREF_BIBR, Notch and RTK signaling pathway XREF_BIBR.
USP5 affects IFNB
| 1 2
USP5 decreases the amount of IFNB.
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USP5 decreases the amount of IFNB. 2 / 2
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Moreover, USP5 suppresses IFNb expression and enhances VSV replication by recruiting STUB1 to degrade RIG-I (40) .

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In addition, a recent systematic functional screening assay revealed that USP5 inhibits IFNb expression and promotes VSV replication by recruiting STIP1 homology and Ubox containing protein 1 (STUB1) to degrade RIG-I (40) .
USP5 inhibits IFNB.
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USP5 inhibits IFNB. 1 / 1
| 1

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In addition , a recent systematic functional screening assay revealed that USP5 inhibits IFNbeta expression and promotes VSV replication by recruiting STIP1 homology and U-box containing protein 1 ( STUB1 ) to degrade RIG-I ( 40 ) .
USP5 affects ELAVL1
| 1 2
USP5 inhibits ELAVL1.
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USP5 inhibits ELAVL1. 2 / 2
| 1 1

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MAFG-AS1 direct binding to HuR could recruit USP5 to prevent HuR from degrading by ubiquitination ; BUC patients with high levels of MAFG-AS1 have poor prognosis ; lncRNA MAFG-AS1 is correlated with aggressive characteristics of BUC ; Cell transfection Plasmids for overexpression MAFG-AS1 were purchased from GeneChem Biotechnology ( Shanghai , China ) .
| PMC

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Mechanistically, MAFG-AS1 direct binding to Hu antigen R (HuR) could recruit ubiquitin specific proteinase 5 (USP5) to prevent HuR from degrading by ubiquitination.
| PMC
USP5 increases the amount of ELAVL1.
| 1
USP5 increases the amount of ELAVL1. 1 / 1
| 1

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Among the selected enzymes, knockdown of USP5 repressed the protein level of HuR the most.
| PMC
USP5 affects CAV3
| 3
USP5 decreases the amount of CAV3.
| 2
USP5 decreases the amount of CAV3. 2 / 2
| 2

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Knockdown of USP5 via shRNA or preventing its association with the channel by using Tat epitope fused disruptor peptides decreased Cav3.2 protein levels and produced analgesia in models of inflammatory and neuropathic pain in mice.

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Knockdown of USP5 via shRNA increases Cav3.2 ubiquitination, decreases Cav3.2 protein levels, and reduces Cav3.2 whole-cell currents.
USP5 activates CAV3.
| 1
USP5 activates CAV3. 1 / 1
| 1

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Furthermore, it is revealed recently that USP5 is able to modulate neuropathic and inflammatory pain by enhancing Cav3.2 channel activity [8,9].
USP5 affects CTNNB1
| 1 2
USP5 inhibits CTNNB1.
| 1
USP5 inhibits CTNNB1. 1 / 1
| 1

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Taken together , these findings indicated that USP5 prevented beta-catenin degradation by inhibiting its ubiquitination and regulated the Wnt / beta-catenin signaling pathway to promote EMT in NSCLC cells .
USP5 increases the amount of CTNNB1.
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USP5 increases the amount of CTNNB1. 1 / 1
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In the experiments of overexpression, USP5 promoted the proliferation of trophoblast cells, and up-regulated the expressions of beta-catenin and the downstream signals c-Myc and Cyclin D1 in trophoblast cells.
USP5 activates CTNNB1.
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USP5 activates CTNNB1. 1 / 1
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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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Moreover, inhibiting USP5 by genetic shRNA or small molecule inhibitors such as WP1130 leads to MM cell apoptosis [8] .

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Moreover, inhibiting USP5 by genetic shRNA or small molecule inhibitors such as WP1130 leads to MM cell apoptosis [ xref ].
Hsa-miR-3919 affects USP5
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Hsa-miR-3919 decreases the amount of USP5. 2 / 2
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Bortezomib affects USP5
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Bortezomib increases the amount of USP5. 2 / 2
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In DRG-derived ND7/23 cells, bortezomib increased protein levels of Ca v 3.2 and T-channel-dependent currents, as assessed by a patch-clamp method, but did not upregulate expression of Ca v 3.2 mRNA or USP5 protein.

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No evidence text available
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Knockdown of the mammalian IsoT (USP5) causes a similar accumulation of polyubiquitin as well as an increase in the proteasomal substrate p53 [XREF_BIBR].

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The mutation of ubp14 and the usp5 homologues in Saccharomyces cerevisiae, Dictyostelium, and Arabidopsis causes accumulation of free polyubiquitin XREF_BIBR, XREF_BIBR, XREF_BIBR.

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Suppression deubiquitinase USP5 inhibits the inflammatory response of chronic periodontitis by suppressing STAT3 signaling.

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Inhibition of deubiquitinase USP5 suppresses STAT3 signaling and attenuates the inflammatory response of chronic periodontitis.
USP5 affects cell death
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Our previous studies showed that targeting USP5 leads to c-Maf degradation and MM cell death, suggesting that the USP5 and c-Maf axis is a potential therapeutic target in MM [8].

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Our previous studies showed that targeting USP5 leads to c-Maf degradation and MM cell death, suggesting that the USP5 and c-Maf axis is a potential therapeutic target in MM [XREF_BIBR].
USP5 affects Neoplasms
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Furthermore, knockdown of USP5 in U251 cells remarkably inhibited tumor growth in vivo .

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It has been reported that USP5 promotes tumor proliferation and tumorigenesis through the deubiquitination of histone deacetylase 2 ( HDAC2 ) ( Du et al ., 2019 ) and beta-catenin ( Ma et al ., 2018 ) .
USP5 affects JNK
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USP5 inhibits JNK. 2 / 2
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Loss of usp5 activates apoptosis and the JNK pathway.

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Second, loss of usp5 activates apoptosis and the JNK pathway.

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Inhibition of deubiquitinase USP5 suppresses STAT3 signaling and attenuates the inflammatory response of chronic periodontitis.

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Suppression deubiquitinase USP5 inhibits the inflammatory response of chronic periodontitis by suppressing STAT3 signaling.
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Usp5 knockdown suppressed cell viability and induced apoptosis in HCC cells.

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USP5 is up-regulated in pancreatic cancer tissue and promotes cell viability and proliferation.
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It has been reported that USP5 promotes tumor proliferation and tumorigenesis through the deubiquitination of histone deacetylase 2 ( HDAC2 ) ( Du et al ., 2019 ) and beta-catenin ( Ma et al ., 2018 ) .

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USP5 expression promotes tumorigenesis in many cancers , like in non-small cell lung cancer overexpression of USP5 stabilizes the beta-catenin protein [ 13 ] .
UBTD2 affects USP5
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UBTD2 activates USP5. 2 / 2
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In conclusion, DC-UbP mediates USP5 and UbE1 to form a functionally dynamic complex that plays a regulatory role in facilitating the efficiency of ubiquitination and deubiquitination in cellular metabolism.

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Thus, DC-UbP modulates the cellular levels of ubiquitinated conjugates by coordinating USP5 and UbE1.
TRPV1 affects USP5
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TRPV1 activates USP5. 2 / 2
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TRPV1 Nociceptor Activity Initiates USP5 and T-type Channel Mediated Plasticity.

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TRPV1 Nociceptor Activity Initiates USP5/T-type Channel-Mediated Plasticity.
FUT1 affects USP5
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FUT1 inhibits USP5. 2 / 2
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In contrast, Ub activated IPaseT is inhibited by Ub-H through a three-step process.

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We also determined the kinetics of inhibition of IPaseT by Ub-H.
Triclosan affects USP5
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Triclosan increases the amount of USP5.
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Triclosan increases the amount of USP5. 1 / 1
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Triclosan decreases the amount of USP5.
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Triclosan decreases the amount of USP5. 1 / 1
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Sodium arsenite increases the amount of USP5.
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Sodium arsenite increases the amount of USP5. 1 / 1
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Sodium arsenite decreases the amount of USP5.
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Sodium arsenite decreases the amount of USP5. 1 / 1
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Flutamide affects USP5
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Flutamide increases the amount of USP5.
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Flutamide increases the amount of USP5. 1 / 1
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Flutamide decreases the amount of USP5.
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Flutamide decreases the amount of USP5. 1 / 1
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No evidence text available
USP5 affects calcium(2+)
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USP5 inhibits calcium(2+).
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CPA at 400mg/kg alone or TPEN plus CPA at 200mg/kg caused Ca v 3.2 overexpression accompanied by upregulation of Egr-1 and USP5, known to promote transcriptional expression and reduce proteasomal degradation of Ca v 3.2, respectively, in the dorsal root ganglia (DRG).
USP5 activates calcium(2+).
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This would add to the already elevated level of USP5, which would enhance the deubiquitinylation of Ca 3.2 and further potentiate the expression of the channel in the plasma membrane.Asparagine (N)-linked glycosylation is another type of post-translational modification that has been reported to potentially contribute to peripheral painful diabetic neuropathy.
USP5 affects USP5
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USP5 inhibits USP5.
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USP5 inhibits USP5. 1 / 1
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Mebendazole synergizes with WP1130, an inhibitor of USP5, because mebendazole downregulates USP5 expression and WP1130 inhibits USP5 deubiquitinase activity.
USP5 increases the amount of USP5.
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USP5 increases the amount of USP5. 1 / 1
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Furthermore, IHC analyses showed that USP5 knockdown significantly decreased the expression of USP5 and the cell proliferation marker Ki-67 in the xenografts of mice.
USP5 affects TRIM6
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USP5 inhibits TRIM6.
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USP5 inhibits TRIM6. 1 / 1
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Exogenous IsoT expression disrupted the TRIM6 punctate structures, without affecting TRIM6-IKKepsilon co-localization (XREF_SUPPLEMENTARY), as well as in vitro treatment with IsoT specifically degraded the unanchored poly-Ub chains associated with TRIM6, while not having an effect on covalently ubiquitinated TRIM25 used as a control (XREF_SUPPLEMENTARY).
USP5 decreases the amount of TRIM6.
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Modified USP5 decreases the amount of TRIM6. 1 / 1
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Indeed, in agreement with our hypothesis, co-expression of IsoT decreased the amount of TRIM6 synthesized multimeric Ub interacting with IKKepsilon in a dose dependent manner (XREF_FIG, left panel).
USP5 affects SMURF1
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USP5 decreases the amount of SMURF1.
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Mutated USP5 decreases the amount of SMURF1. 1 / 1
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For instance, both the wild-type and enzymatically inactive mutant of USP5 can cause a decreased polyubiquitination level of SMURF1 (112), which suggest that USP5 functions in the immune response probably independently of its protease activity.
USP5 activates SMURF1.
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USP5 activates SMURF1. 1 / 1
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USP5 enhances the stability and turnover of SMURF1 via decreasing its polyubiquitin expression level, which caused STAT1 to decrease.
USP5 affects MDM2
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USP5 increases the amount of MDM2.
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Modified USP5 increases the amount of MDM2. 1 / 1
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Conversely, Usp5 overexpression suppressed the expression of p14 ARF and p53 and promoted Mdm2 expression, leading to inactivation of this signaling.
USP5 decreases the amount of MDM2.
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Modified USP5 decreases the amount of MDM2. 1 / 1
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Conversely, Usp5 overexpression suppressed the expression of p14 ARF and p53 and promoted Mdm2 expression, leading to inactivation of this signaling.
USP5 affects HDAC2
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USP5 decreases the amount of HDAC2.
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USP5 decreases the amount of HDAC2. 1 / 1
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Knockdown of USP5 decreased histone deacetylase 2 (HDAC2) expression and increased p27 (an important cell cycle inhibitor) expression in vitro and in vivo.
USP5 activates HDAC2.
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USP5 activates HDAC2. 1 / 1
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Macrophage-derived extracellular vesicles regulates USP5-mediated HDAC2/NRF2 axis to ameliorate inflammatory pain.
USP5 affects DNA Damage
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USP5 inhibits DNA Damage.
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USP5 knockdown leads to DNA damage, cell cycle arrest and apoptosis in PDAC cells.
USP5 activates DNA Damage.
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USP5 deficiency also induces DNA damage, cell cycle arrest and apoptosis in pancreatic ductal adenocarcinoma cells.
USP5 affects CDH1
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USP5 decreases the amount of CDH1.
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USP5 decreases the amount of CDH1. 1 / 1
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In vitro experimental results further proved that the depletion of USP5 reduced the expression of E-cadherin and inhibited the migration of HCC cells.
USP5 activates CDH1.
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USP5 activates CDH1. 1 / 1
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Knockdown USP5 increased the fluorescence intensity of E-cadherin but reduced that of Vimentin, and the results was opposite in USP5 overexpressed cells.
TNFSF10 affects USP5
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TNFSF10 inhibits USP5.
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TNFSF10 inhibits USP5. 1 / 1
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TRAIL treatment in cancer cells reduced the activity and cleavage of USP5, a deubiquitinase (DUB) previously shown to target unanchored Ub polymers and regulate p53 mediated transcription.
TNFSF10 activates USP5.
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TNFSF10 activates USP5. 1 / 1
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Together, we conclude that activated TRAIL enhances USP5 activity and induces apoptosis in TRAIL sensitive and -resistant cells.
Peripheral Nerve Injuries increases the amount of USP5.
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Peripheral Nerve Injuries increases the amount of USP5. 1 / 1
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Overall, our observations extend our previous findings showing that peripheral nerve injury upregulates USP5 levels and leads to an enhanced interaction between USP5 and Cav3.2 [6].

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Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased pain sensitivity.
17alpha-ethynylestradiol increases the amount of USP5.
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17alpha-ethynylestradiol increases the amount of USP5. 1 / 1
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ctd
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17alpha-ethynylestradiol decreases the amount of USP5.
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17alpha-ethynylestradiol decreases the amount of USP5. 1 / 1
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Warfarin affects USP5
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Warfarin decreases the amount of USP5. 1 / 1
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Valproic acid decreases the amount of USP5. 1 / 1
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Valdecoxib affects USP5
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Valdecoxib increases the amount of USP5. 1 / 1
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Trimellitic anhydride increases the amount of USP5. 1 / 1
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No evidence text available
Thiram affects USP5
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Thiram decreases the amount of USP5. 1 / 1
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No evidence text available
Tetrodotoxin affects USP5
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Tetrodotoxin decreases the amount of USP5. 1 / 1
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Moreover and consistent with an effect of IL-1β that is mediated by neuronal activity, tetrodotoxin co-treatment (1 µM; overnight) in DRG cell cultures attenuated IL-1β-induced USP5 protein expression by 61.2 ± 2.8% (n = 2 cultures).
Tetraarsenic tetrasulfide increases the amount of USP5. 1 / 1
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No evidence text available
Sunitinib affects USP5
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Sunitinib decreases the amount of USP5. 1 / 1
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No evidence text available
Sub affects USP5
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Sub activates USP5. 1 / 1
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To understand the roles of unanchored and substrate conjugated (anchored) chains in Tax induced IKK activation, cell-free assays were performed in the presence of Isopeptidase T (IsoT), a DUB specific for unanchored chains, or the OTU domain of the L protein of Crimean Congo hemorrhagic fever virus (viral OTU), a DUB specific for substrate anchored chains.
Quinocetone affects USP5
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Quinocetone decreases the amount of USP5. 1 / 1
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No evidence text available
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The protease inhibitor N-ethylmaleimide (NEM) inhibited the ability of HBx, GST-HBx and IsoT to cleave Lys63-linked tetra-ubiquitin chains, consistent with HBx being a cysteine protease (Fig. 2C ).
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Inhibitors of UCH family DUBs have been reported with modest selectivity and affinity, and J-series prostaglandins have been reported to inhibit IsoT.
1 |
Pirinixic acid increases the amount of USP5. 1 / 1
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No evidence text available
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Piperonyl butoxide increases the amount of USP5. 1 / 1
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No evidence text available
Phorbol affects USP5
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Phorbol activates USP5. 1 / 1
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This structural difference is believed to ac- count for the finding that atypical isot ' orms of PKC are not activated by DAG or phorbol esters (Ways et al., 1992; Nakanishi and Exton, 1992 : SeiNe et[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Pentachlorophenol increases the amount of USP5. 1 / 1
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Paclitaxel affects USP5
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Paclitaxel decreases the amount of USP5. 1 / 1
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Nimesulide affects USP5
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Nimesulide increases the amount of USP5. 1 / 1
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Nickel monoxide increases the amount of USP5. 1 / 1
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Nefazodone affects USP5
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Nefazodone increases the amount of USP5. 1 / 1
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Methyltestosterone increases the amount of USP5. 1 / 1
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Methylazoxymethanol increases the amount of USP5. 1 / 1
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Methyl methanesulfonate increases the amount of USP5. 1 / 1
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Lovastatin affects USP5
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Lovastatin decreases the amount of USP5. 1 / 1
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No evidence text available
Ketone body affects USP5
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Ketone body increases the amount of USP5. 1 / 1
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ctd
No evidence text available
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Hsa-miR-96-5p decreases the amount of USP5. 1 / 1
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Hsa-miR-8080 affects USP5
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Hsa-miR-8080 decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-6770-5p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-6501-3p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-525-5p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-520a-5p decreases the amount of USP5. 1 / 1
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No evidence text available
Hsa-miR-484 affects USP5
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Hsa-miR-484 decreases the amount of USP5. 1 / 1
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No evidence text available
Hsa-miR-4642 affects USP5
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Hsa-miR-4642 decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-455-3p decreases the amount of USP5. 1 / 1
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No evidence text available
Hsa-miR-4318 affects USP5
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Hsa-miR-4318 decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-3180-5p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-30a-5p decreases the amount of USP5. 1 / 1
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No evidence text available
Hsa-miR-23c affects USP5
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Hsa-miR-23c decreases the amount of USP5. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-miR-23b-3p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-23a-3p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-223-5p decreases the amount of USP5. 1 / 1
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No evidence text available
1 |
Hsa-miR-182-5p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-130a-5p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-1271-5p decreases the amount of USP5. 1 / 1
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No evidence text available
1 |
Hsa-miR-1260b decreases the amount of USP5. 1 / 1
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No evidence text available
Hsa-miR-1256 affects USP5
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Hsa-miR-1256 decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-1250-3p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-124-3p decreases the amount of USP5. 1 / 1
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No evidence text available
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Hsa-miR-1180-3p decreases the amount of USP5. 1 / 1
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No evidence text available
Hexabromocyclododecane increases the amount of USP5. 1 / 1
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No evidence text available
Gold atom affects USP5
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Gold atom decreases the amount of USP5. 1 / 1
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USP5 Promoted EMT, Invasion, and Migration in NSCLC Cells.
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No evidence text available
En affects USP5
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En increases the amount of USP5. 1 / 1
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En-Gal4 was crossed with UAS-usp5 to induce usp5 overexpression in the posterior compartment of the wing disc.
Doxorubicin affects USP5
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The cells were transfected with siUsp5 or pUsp5, then treated with 2.0 muM Doxorubicin (Dox) and 10muM Cisplatin (Cis), which are two common anti-cancer chemotherapy drugs.

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This structural difference is believed to ac- count for the finding that atypical isot ' orms of PKC are not activated by DAG or phorbol esters (Ways et al., 1992; Nakanishi and Exton, 1992 : SeiNe et[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Cyclophosphamide hydrate increases the amount of USP5. 1 / 1
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No evidence text available
Coumestrol affects USP5
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Coumestrol increases the amount of USP5. 1 / 1
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No evidence text available
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Copper(II) sulfate decreases the amount of USP5. 1 / 1
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No evidence text available
Chalcone affects USP5
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RA-9, a chalcone derivative with a structure similar to b-AP15, was reported to inhibit proteasomal DUBs [XREF_BIBR] as well as UCHL1, UCHL3, USP2, USP5, and USP8 [XREF_BIBR].
Capsaicin affects USP5
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Capsaicin decreases the amount of USP5. 1 / 1
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ctd
No evidence text available
Acrylamide affects USP5
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Acrylamide increases the amount of USP5. 1 / 1
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No evidence text available
Acetamide affects USP5
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Acetamide decreases the amount of USP5. 1 / 1
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ctd
No evidence text available
Abrine affects USP5
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Abrine decreases the amount of USP5. 1 / 1
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ctd
No evidence text available
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To determine whether USP5 had the potential to promote migration and invasion , wound-healing and transwell invasion assays were performed using NSCLC cells .
USP5 affects vemurafenib
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In addition, Usp5 KD reduced the vemurafenib IC50 concentration in A375 cells by ~ 2-fold.

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USP5 targets the transcription factor SLUG and then induces EMT in hepatocellular carcinoma cells.
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This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the pain pathway.
USP5 affects proteolysis
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Isopeptidase T stimulates protein degradation in a system reconstituted from purified enzyme components.
USP5 affects picloram
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( A ) Downregulated USP5 ubiquitination leads to increased USP5 expression , which promotes RIG-I K11 ubiquitination modification and inhibits the IFN-I pathways by recruiting STUB1 .
USP5 affects pdaC
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USP5 activates pdaC. 1 / 1
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Therefore, we hypothesized that FoxM1 was involved in USP5 mediated tumor progression of PDAC.
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By contrast, USP5 overexpression significantly promoted cell migration and cell mitosis.

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USP5 deficiency also induces DNA damage , cell cycle arrest and apoptosis in pancreatic ductal adenocarcinoma cells ( 51 , 53 ) .
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By contrast, USP5 overexpression significantly promoted cell migration and cell mitosis.

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Loss of usp5 causes severe mid differentiation defects in photoreceptors.
USP5 affects VIM
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USP5 inhibits VIM. 1 / 1
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Knockdown USP5 increased the fluorescence intensity of E-cadherin but reduced that of Vimentin, and the results was opposite in USP5 overexpressed cells.
USP5 affects TAB2
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USP5 activates TAB2. 1 / 1
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The TAB2 associated proteins were treated with IsoT, then immunoblotted with an antibody against Ub, IRAK1 or TRAF6.
USP5 affects STAT1
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USP5 inhibits STAT1. 1 / 1
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In the case of IFNAR1-mediated downstream signaling, BRCC36 sustains the protein turnover of IFNAR1 by removing K63-Ub from IFNAR1 (109), whereas USP5 has been identified to negatively regulate IFN-I-induced p-STAT1 activation and antiviral activities by removing K63-Ub on SMURF1 (112).
USP5 affects SLC22A3
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USP5 activates SLC22A3. 1 / 1
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USP5 Promotes Metastasis in Non Small Cell Lung Cancer by Inducing Epithelial-Mesenchymal Transition via Wnt and beta-Catenin Pathway.
USP5 affects Proteasome
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Local administration of NO may prevent neointimal hyperplasia by inhibiting isopeptidase T levels and activity in the vasculature, thereby inhibiting the 26S proteasome in VSMCs.
USP5 affects Protease
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Mutated USP5 decreases the amount of Protease. 1 / 1
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For instance, both the wild-type and enzymatically inactive mutant of USP5 can cause a decreased polyubiquitination level of SMURF1 (112), which suggest that USP5 functions in the immune response probably independently of its protease activity.
| 1

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Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination.
| 1

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Although isoT moderately reduced the MAVS polymerization activity , this could be due to partial degradation of anchored Ubn by isoT ( as observed in Figure 2F ) .
USP5 affects Neuralgia
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Importantly, the authors showed that prophylactic knockdown of USP5, or prophylactic disruption of the Ca 3.2/USP5 complex, was sufficient to prevent nerve-injury-induced mechanical and thermal hyperalgesia demonstrating the causal implication of the ubiquitinylation machinery in the development of neuropathic pain in this experimental model.
USP5 affects NLRP3
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USP5 inhibits NLRP3. 1 / 1
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USP5 attenuates NLRP3 inflammasome activation by promoting autophagic degradation of NLRP3.

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USP5 attenuates NLRP3 inflammasome activation by promoting autophagic degradation of NLRP3.
| 1

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Interestingly, USP5 silence led to apoptosis of MM cells expressing c-Maf but not MM cells lacking c-Maf, indicating c-Maf is a key factor in USP5 mediated MM cell proliferation and survival.
USP5 affects MAVS
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USP5 inhibits MAVS. 1 / 1
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Strikingly, the reaction mixture showed a potent activity in inducing MAVS aggregation and activation when RIG-I was supplemented (XREF_FIG, Lane 4), which could be abolished by IsoT treatment (XREF_FIG, Lane 3).
USP5 affects MAP3K7
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USP5 inhibits MAP3K7. 1 / 1
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As shown in XREF_FIG, both CYLD and IsoT effectively converted K63 polyUb chains into mono-Ub and completely blocked the activation of TAK1.
USP5 affects JUN
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USP5 inhibits JUN. 1 / 1
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Recently, it has been shown that Usp5 knockdown induces p53 activation [XREF_BIBR], and Usp5 controls activation of apoptotic signaling as well as Jun N-Terminal kinase pathway during eye development [XREF_BIBR].
USP5 affects IRF3
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USP5 activates IRF3. 1 / 1
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This preparation promoted IRF3 dimerization, but lost its activity when treated with the deubiquitination enzyme IsoT.
USP5 affects IKK_complex
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Importantly, the IsoT treatment abrogated IKK activation, indicating that the Ubc5 synthesized unanchored polyUb chains, but not ubiquitinated TRAF6, directly activated the kinase.
USP5 affects IFIT2
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USP5 inhibits IFIT2. 1 / 1
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Furthermore, IsoT co-expression reduced the TRIM6 dependent ISG54 reporter activation almost to the level of the control without TRIM6 (XREF_FIG), suggesting that unanchored Ub chains are important for TRIM6 dependent IKKepsilon enhancement.
USP5 affects Hyperalgesia
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Importantly, the authors showed that prophylactic knockdown of USP5, or prophylactic disruption of the Ca 3.2/USP5 complex, was sufficient to prevent nerve-injury-induced mechanical and thermal hyperalgesia demonstrating the causal implication of the ubiquitinylation machinery in the development of neuropathic pain in this experimental model.
USP5 affects HPN
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USP5 inhibits HPN. 1 / 1
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Furthermore, USP5 overexpression significantly rescued the suppressive effect of Hpn on the viability of HCC cells.
USP5 affects HNRNPA1
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USP5 activates HNRNPA1. 1 / 1
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Deubiquitinating enzyme USP5 modulates hnRNPA1 at post-translational step via interaction dependent subsequent hnRNPA1 stabilization.
USP5 affects FLAG
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USP5 activates FLAG. 1 / 1
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To confirm modulation of vemurafenib activity by Usp5, A375 control, Usp5 KD (Usp5 shRNA) and Usp5 overexpressing (Usp5 FLAG) cells were left untreated or treated with vemurafenib before examining Usp5 expression, activity, p53 protein levels and apoptosis.
USP5 affects Cyclin
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USP5 activates Cyclin. 1 / 1
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Deubiquitinase USP5 promotes non-small cell lung cancer cell proliferation by stabilizing cyclin D1.
USP5 affects Caspase
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USP5 activates Caspase. 1 / 1
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Usp5 KD enhanced caspase activation, primarily through increased caspase 8 activation in both p53 wild-type and mutant cells.

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Deubiquitinase USP5 promotes non-small cell lung cancer cell proliferation by stabilizing cyclin D1.
USP5 affects CRC
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USP5 activates CRC. 1 / 1
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While USP5 knockdown effectively inhibited CRC cell growth, overexpressed USP5 promoted the growth of CRC cells and made them more resistant to doxorubicin (DOX).
USP5 affects CCND1
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USP5 increases the amount of CCND1. 1 / 1
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Overexpression of USP5 could significantly extend the half-life of CyclinD1, while knockdown of USP5 decreased the protein level of CyclinD1, which could be restored by proteasome inhibitor MG-132.
USP5 affects CAT
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USP5 activates CAT. 1 / 1
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Saturation of a DUB, USP5, with the beta-grasp domain of ubiquitin also enhanced the k cat (XREF_FIG).
USP5 affects BCHE
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USP5 activates BCHE. 1 / 1
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The only detectable cross-reactivities were the labeling of USP5 (Isopeptidase T) and an ATP dependent assembly of polyOTULIN ABP chains via Ub activating E1 enzymes.
USP5 affects Analgesia
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In addition and consistent with the essential role of Cav3.2 channels in pain signalling , in vivo knockdown of USP5 mediated analgesia in both inflammatory and neuropathic mouse models of mechanical hypersensitivity [ 134 ] .
Sesame Oil affects USP5
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Sesame Oil decreases the amount of USP5. 1 / 1
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SRSF1 affects USP5
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SRSF1 activates USP5. 1 / 1
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Additionally , knockdown of SF2 / ASF1 leads to more USP5 expression is new observation , where with siUSP5 in combination it sensitizes cells to undergo more Caspase cascade activation ( Fig. 6 A , B , C ) .
S1 affects USP5
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S1 activates USP5. 1 / 1
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It is known that occupancy of the S1 ' site by the proximal ubiquitin activates USP5 and that the C-terminal glycine (G76) of this ubiquitin is determinant for this activation XREF_BIBR XREF_BIBR.
PKM affects USP5
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PKM activates USP5. 1 / 1
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Our results are notable for the low number of gene targets uncovered, three (RTN4, ATP2B4, and USP5), and the absence of the previously reported PTBP1 target PKM2 [XREF_BIBR, XREF_BIBR].
OTU affects USP5
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OTU activates USP5. 1 / 1
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To understand the roles of unanchored and substrate conjugated (anchored) chains in Tax induced IKK activation, cell-free assays were performed in the presence of Isopeptidase T (IsoT), a DUB specific for unanchored chains, or the OTU domain of the L protein of Crimean Congo hemorrhagic fever virus (viral OTU), a DUB specific for substrate anchored chains.
N-methyl-4-phenylpyridinium increases the amount of USP5. 1 / 1
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The protease inhibitor N-ethylmaleimide (NEM) inhibited the ability of HBx, GST-HBx and IsoT to cleave Lys63-linked tetra-ubiquitin chains, consistent with HBx being a cysteine protease (Fig. 2C ).
MYCN affects USP5
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MYCN increases the amount of USP5. 1 / 1
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MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells.
MCF2L2 affects USP5
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MCF2L2 decreases the amount of USP5. 1 / 1
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Moreover and consistent with an effect of IL-1β that is mediated by neuronal activity, tetrodotoxin co-treatment (1 µM; overnight) in DRG cell cultures attenuated IL-1β-induced USP5 protein expression by 61.2 ± 2.8% (n = 2 cultures).
LI affects USP5
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LI activates USP5. 1 / 1
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All experiments were performed in triplicate and repeated at least twice.The building blocks 1 and 3 (Figure 2 ) for isoA 1 and isoT 1 were synthesized following the previously reported protocol by Li et al. [18] .
ICG 001 affects USP5
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ICG 001 decreases the amount of USP5. 1 / 1
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Halogenated Diphenyl Ethers decreases the amount of USP5. 1 / 1
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HNRNPA1 affects USP5
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HNRNPA1 activates USP5. 1 / 1
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This means hnRNPA1 is a downstream target of USP5, thereafter affecting SF2 and ASF1 expression level in absence of hnRNPA1.
H2ax affects USP5
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H2ax inhibits USP5. 1 / 1
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H2A.X in Western blot analyses in response to doxycycline induced USP5 knockdown.
GW 7647 affects USP5
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GW 7647 inhibits USP5. 1 / 1
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Moreover, GW7647 did not inhibit USP5 and USP8.
GSK-J4 affects USP5
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GSK-J4 decreases the amount of USP5. 1 / 1
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FOXM1 affects USP5
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FOXM1 activates USP5. 1 / 1
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Additionally, we found that overexpression of USP5 stabilized the FoxM1 protein in PDAC cells and FoxM1 rescued the inhibitory effect of USP5 knockdown in USP5 depleted cells.
FAS affects USP5
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FAS inhibits USP5. 1 / 1
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A small molecule DUB inhibitor (EOAI3402143) phenocopied the FAS induction and apoptotic sensitization of Usp5 knockdown and fully blocked melanoma tumor growth in mice.

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Similar results were obtained in A375R Usp5 KD cells treated with a MEK inhibitor (XREF_SUPPLEMENTARY).
DESI1 affects USP5
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DESI1 desumoylates USP5. 1 / 1
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It has recently been found that SUMO protease includes desumoylating isopeptidase 1 (DESI1), desumoylating isopeptidase 2 (DESI2) and ubiquitin-specific protease-like 1 (USPL1) ( xref ).
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D-glucopyranose decreases the amount of USP5. 1 / 1
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CRC affects USP5
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CRC activates USP5. 1 / 1
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While USP5 knockdown effectively inhibited CRC cell growth, overexpressed USP5 promoted the growth of CRC cells and made them more resistant to doxorubicin (DOX).
CNTLN affects USP5
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CNTLN inhibits USP5. 1 / 1
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This discrepancy in centrosomal protein stability may result from the ability of WP1130 to inhibit USP5, USP14, and UCH37 in addition to USP9X.
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C646 compound decreases the amount of USP5. 1 / 1
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C60 fullerene increases the amount of USP5. 1 / 1
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Brodifacoum affects USP5
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Brodifacoum increases the amount of USP5. 1 / 1
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BASP1 affects USP5
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BASP1 inhibits USP5. 1 / 1
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The parent compound NAP (1000 mumol/L), used as a negative control, only slightly inhibited isopeptidase T activity (17%, P <.02) compared with baseline.
ANXA1 affects USP5
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ANXA1 inhibits mutated USP5. 1 / 1
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We found that over-expression of p35 can rescue the Elav reduced phenotype in the usp5 mutant clone of the eye disc (XREF_FIG).
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3-cyanoalanine increases the amount of USP5. 1 / 1
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2-hydroxypropanoic acid decreases the amount of USP5. 1 / 1
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DTT significantly prevented SNAP mediated inhibition of isopeptidase T activity, restoring activity to 77.8% of control (* P <.001 vs control; ** P <.001 vs SNAP) (XREF_FIG).

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