USP42 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 42
HGNC Gene Symbol
USP42
Identifiers
hgnc:20068 NCBIGene:84132 uniprot:Q9H9J4
Orthologs
mgi:1924050 rgd:1305231
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP42
Number of Papers
28 retrieved on 2022-05-22

DepMap Analysis

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

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

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type
TP53 tumor protein p53 -0.286 BioGRID IntAct Pathway Commons INDRA (3) Reactome (4) 0.09 0.43 1.51e-01
OCM oncomodulin 0.254
PPM1D protein phosphatase, Mg2+/Mn2+ dependent 1D 0.243 0.43 2.29 6.97e-07
MDM2 MDM2 proto-oncogene 0.24 Pathway Commons INDRA (1) Reactome (4) -0.15 -0.92 7.30e-02
TARS2 threonyl-tRNA synthetase 2, mitochondrial -0.239 Reactome (1) 0.13 0.60 4.51e-02
UQCRB ubiquinol-cytochrome c reductase binding protein -0.238 -0.01 -0.13 9.31e-01
FAM220A family with sequence similarity 220 member A 0.237

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP42using 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:0030330 DNA damage response, signal transduction by p53 class mediator Biological Process 3.35e-06 1.35e-03 3.45e-04
GO:0042770 signal transduction in response to DNA damage Biological Process 6.48e-06 2.62e-03 3.45e-04
GO:0046827 positive regulation of protein export from nucleus Biological Process 1.75e-05 7.05e-03 6.19e-04
GO:0071480 cellular response to gamma radiation Biological Process 3.37e-05 1.36e-02 8.02e-04
GO:0097718 disordered domain specific binding Molecular Function 4.12e-05 1.66e-02 8.02e-04
GO:0031668 cellular response to extracellular stimulus Biological Process 5.28e-05 2.13e-02 8.02e-04
GO:0072331 signal transduction by p53 class mediator Biological Process 5.28e-05 2.13e-02 8.02e-04
GO:0046825 regulation of protein export from nucleus Biological Process 6.47e-05 2.61e-02 8.59e-04
GO:0071496 cellular response to external stimulus Biological Process 1.05e-04 4.24e-02 1.24e-03
GO:0010332 response to gamma radiation Biological Process 1.23e-04 4.96e-02 1.31e-03

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP42 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP42 deubiquitinates TP53. 6 / 6
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It has been reported that USP42 interacts with and deubiquitinates p53.

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In the initial phases of a stress response, USP42 deubiquitinates p53 by forming a direct complex with p53.

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During the early phase of response to a stress signal, USP42 preferentially makes up a complex with and deubiquitinates p53, leading to the rapid activation of p53 for cell cycle arrest and p53-dependent transcription [55].
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P53 can be directly deubiquitinated by Usp42 which reverses its ubiquitination by MDM2 [XREF_BIBR].

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This is accomplished by several deubiquitination enzymes including USP7 that deubiquitinates Mdm2 to stabilize p53 [XREF_BIBR] as well as USP10 and USP42 that can directly deubiquitinate p53 upon DNA damage [XREF_BIBR, XREF_BIBR].
USP42 deubiquitinates MMP9. 1 / 1
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USP42 deubiquitinates Histone_H2B. 1 / 1
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Indeed, in vitro analysis showed that USP42 is able to efficiently deubiquitylate histone H2B (XREF_FIG, E and F).
USP42 deubiquitinates H2BC10. 1 / 1
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Depletion of USP42 increased H2B ubiquitylation at a model promoter and decreased both basal and induced transcription from a number of promoters.

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach

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To further explore the cellular mechanism underlying USP42 induced cell proliferation, the protein levels of cell cycle proteins were assessed.

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USP42 is highly expressed in GC tissue and conspicuously associated with the tumor size , TNM staging , lymph node metastasis , and OS rate of GC patients , while inhibition of USP42 can induce G0 / G1 block and suppress cell proliferation and invasion ( Hou et al ., 2016 ) .

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Moreover, USP42 silencing in two GC cell lines, AGS and MKN-45, notably inhibited cell proliferation, but stimulated G1 phase arrest.

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USP42 is highly expressed in GC tissue and conspicuously associated with the tumor size, TNM staging, lymph node metastasis, and OS rate of GC patients, while inhibition of USP42 can induce G0/G1 block and suppress cell proliferation and invasion.

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Our in vitro findings showed that silencing of USP42 inhibited cell proliferation via inducing G0/G1 arrest and suppressed cell invasion via MMPs and EMT regulators.

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Our in vitro findings showed that silencing of USP42 inhibited cell proliferation via inducing G0/G1 arrest and suppressed cell invasion via MMPs and EMT regulators.
USP42 affects Wnt
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USP42 inhibits Wnt. 5 / 5
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Accordingly , USP42 increases the turnover of LRP6 and Frizzled ( FZD ) receptors and inhibits Wnt signalling .

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Accordingly, USP42 increases the turnover of LRP6 and Frizzled (FZD) receptors and inhibits Wnt signalling.

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USP42 protects ZNRF3 and RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling.

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USP42 protects ZNRF3 / RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling .

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We conclude that USP42 inhibits Wnt signalling in HCT116 cells by destabilising the Wnt receptors , independently of its roles in p53 response to genotoxic stress .
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Valproic acid decreases the amount of USP42. 4 / 4
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USP42 depletion decreased the transcription of most of these target genes, although some (CASP1, PUMA, BAX, PIDD, and WIP1) were not affected (XREF_FIG G).

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To assess how the knockdown of USP42 induces a change in transcription from an endogenous promoter, we investigated the influence of USP42 reduction on the p21 promoter.

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Although we do not find a clear role for USP42 in controlling either the basal or fully activated levels of p53, the function of USP42 is required to allow the rapid activation of p53 dependent transcription and a p53 dependent cell-cycle arrest in response to stress.

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Again, we found three examples of genes that were not significantly affected by USP42 depletion (TAp73, FOXM1, and CCNE1), indicating that the requirement for USP42 to promote transcription is not universal.
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Hsa-miR-7157-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-6838-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-6792-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-6731-3p decreases the amount of USP42. 3 / 3
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Hsa-miR-6088 decreases the amount of USP42. 3 / 3
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Hsa-miR-497-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-4770 decreases the amount of USP42. 3 / 3
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Hsa-miR-4708-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-4503 decreases the amount of USP42. 3 / 3
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Hsa-miR-4482-3p decreases the amount of USP42. 3 / 3
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Hsa-miR-4310 decreases the amount of USP42. 3 / 3
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Hsa-miR-424-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-3686 decreases the amount of USP42. 3 / 3
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Hsa-miR-3607-3p decreases the amount of USP42. 3 / 3
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Hsa-miR-26a-2-3p decreases the amount of USP42. 3 / 3
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Hsa-miR-26a-1-3p decreases the amount of USP42. 3 / 3
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Hsa-miR-195-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-16-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-15b-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-15a-5p decreases the amount of USP42. 3 / 3
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Hsa-miR-143-3p decreases the amount of USP42. 3 / 3
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Hsa-miR-1273f decreases the amount of USP42. 3 / 3
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Hsa-miR-107 affects USP42
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Hsa-miR-107 decreases the amount of USP42. 3 / 3
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Hsa-miR-103a-3p decreases the amount of USP42. 3 / 3
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USP42 affects TP53
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USP42 activates TP53. 3 / 3
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Although we do not find a clear role for USP42 in controlling either the basal or fully activated levels of p53, the function of USP42 is required to allow the rapid activation of p53 dependent transcription and a p53 dependent cell-cycle arrest in response to stress.

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Our previous work showed that USP42 can target p53 for deubiquitylation, with depletion of USP42 resulting in delays in stabilization of p53 and recruitment of p53 to target gene promoters.

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USP42 itself was reported to increase the stability of p53 [XREF_BIBR].
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USP42 is highly expressed in GC tissue and conspicuously associated with the tumor size , TNM staging , lymph node metastasis , and OS rate of GC patients , while inhibition of USP42 can induce G0 / G1 block and suppress cell proliferation and invasion ( Hou et al ., 2016 ) .

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USP42 is highly expressed in GC tissue and conspicuously associated with the tumor size, TNM staging, lymph node metastasis, and OS rate of GC patients, while inhibition of USP42 can induce G0/G1 block and suppress cell proliferation and invasion.

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The USP42 suppressed cells exhibited significantly less invasive potential than the siNC transfected cells (P < 0.01), suggesting that high expression of USP42 enhanced tumor invasiveness.
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Trichostatin A decreases the amount of USP42. 2 / 2
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Hsa-miR-924 affects USP42
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Hsa-miR-924 decreases the amount of USP42. 2 / 2
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Hsa-miR-627-5p decreases the amount of USP42. 2 / 2
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Cyclosporin A increases the amount of USP42. 2 / 2
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USP42 affects MMP
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USP42 increases the amount of MMP.
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USP42 increases the amount of MMP. 1 / 1
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In gastric cancer cells, USP42 is regarded as an invasion promotor since the evidence showed that silencing of USP42 upregulated the expression of the E-cadherin, and downregulated the expression of MMPs, beta-catenin, Twist, and Snail1.
USP42 decreases the amount of MMP.
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USP42 decreases the amount of MMP. 1 / 1
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In gastric cancer cells, USP42 is regarded as an invasion promotor since the evidence showed that silencing of USP42 upregulated the expression of the E-cadherin, and downregulated the expression of MMPs, beta-catenin, Twist, and Snail1.
USP42 affects LRP6
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USP42 inhibits LRP6.
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USP42 inhibits LRP6. 1 / 1
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Consequently, USP42 increases the turnover of Frizzled and LRP6 and diminishes WNT signaling in CRC cells and mouse intestinal organoids [73].
USP42 activates LRP6.
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USP42 activates LRP6. 1 / 1
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Accordingly, USP42 increases the turnover of LRP6 and Frizzled (FZD) receptors and inhibits Wnt signalling.
17alpha-ethynylestradiol increases the amount of USP42.
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17alpha-ethynylestradiol increases the amount of USP42. 1 / 1
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17alpha-ethynylestradiol decreases the amount of USP42.
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17alpha-ethynylestradiol decreases the amount of USP42. 1 / 1
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Urethane affects USP42
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Urethane increases the amount of USP42. 1 / 1
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Tungsten affects USP42
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Tungsten decreases the amount of USP42. 1 / 1
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Triphenyl phosphate decreases the amount of USP42. 1 / 1
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Torcetrapib affects USP42
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Torcetrapib increases the amount of USP42. 1 / 1
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Thiram affects USP42
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Thiram decreases the amount of USP42. 1 / 1
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Sodium arsenite decreases the amount of USP42. 1 / 1
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Pirinixic acid decreases the amount of USP42. 1 / 1
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Pentachlorophenol increases the amount of USP42. 1 / 1
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Paracetamol affects USP42
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Paracetamol decreases the amount of USP42. 1 / 1
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Methyl methanesulfonate increases the amount of USP42. 1 / 1
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Lead diacetate increases the amount of USP42. 1 / 1
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Ionomycin affects USP42
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Ionomycin increases the amount of USP42. 1 / 1
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Indometacin affects USP42
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Indometacin decreases the amount of USP42. 1 / 1
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Hsa-miR-320a decreases the amount of USP42. 1 / 1
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Formaldehyde decreases the amount of USP42. 1 / 1
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Doxorubicin affects USP42
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Doxorubicin decreases the amount of USP42. 1 / 1
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Dorsomorphin decreases the amount of USP42. 1 / 1
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Disulfiram affects USP42
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Disulfiram decreases the amount of USP42. 1 / 1
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Dexamethasone decreases the amount of USP42. 1 / 1
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Copper(II) sulfate increases the amount of USP42. 1 / 1
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Cisplatin affects USP42
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Cisplatin decreases the amount of USP42. 1 / 1
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Bisphenol A affects USP42
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Bisphenol A increases the amount of USP42. 1 / 1
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Acrylamide affects USP42
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Acrylamide decreases the amount of USP42. 1 / 1
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Water Pollutants, Chemical decreases the amount of USP42. 1 / 1
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USP42 affects rich domain
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Mutated USP42 activates rich domain. 1 / 1
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Expression of USP42 mutants targeting the linker domain and the C-terminal lysine rich domain (XREF_FIG B) showed that although the DUB-inactive USP42 C120A mutant retained the ability to bind histone H2B, this interaction was reduced with the DeltaKK mutant and lost with the Deltalinker mutant (XREF_FIG C).

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USP42 enhances homologous recombination repair by promoting R-loop resolution with a DNA-RNA helicase DHX9 .

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We conclude that USP42 prevents EMT in HCT116 cells by inhibiting paracrine Wnt signalling .
USP42 affects doxycycline
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USP42 decreases the amount of doxycycline. 1 / 1
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Interestingly, depletion of USP42 also slightly reduced the basal expression of doxycycline driven GFP and substantially decreased the induced levels of GFP expression following doxycycline treatment of the cells (XREF_FIG, C and D).
USP42 affects cell
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USP42 inhibits cell. 1 / 1
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To investigate whether USP42 inhibits Wnt-driven cell proliferation , we performed spheroid assays , which are more representative for the in vivo growth conditions than 2D cultures , as they recapitulate tumour cell clusters ( Timmins et al , 2004 ) .
USP42 affects cell growth
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Functionally, USP42 downregulation deregulates multiple mRNA splicing events and leads to deterred cancer cell growth, which is consistent with the impact of PLRG1 repression.
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Given the wide range of functions of ZNRF3 / RNF43 in embryogenesis ( Chang et al , 2020 ; Lee et al , 2020 ) , limb development ( Szenker-Ravi et al , 2018 ) , liver zonation ( Planas-Paz et al , 2016 ) , intestinal tract and adrenal gland homeostasis ( Koo et al , 2012 ; Basham et al , 2019 ) and sex determination ( Harris et al , 2018 ) , it would be important to explore whether USP42 also contributes to these biological functions .
USP42 affects USP42
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USP42 decreases the amount of USP42. 1 / 1
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USP42 siRNA suppressed USP42 expression.
USP42 affects TWIST1
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USP42 decreases the amount of TWIST1. 1 / 1
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Transfection of USP42 siRNA significantly reduced the expression levels of beta-catenin, Twist and Snail1, while increasing E-cadherin.
USP42 affects PLRG1
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USP42 activates PLRG1. 1 / 1
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Notably, USP42 directs the integration of the spliceosome component PLRG1 into nuclear speckles, and its depletion interferes with the conformation of SC35 foci.

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Thus, our data indicated that elevated expression of USP42 in GC may promote tumor metastasis and is associated with the clinical outcome of GC patients.
USP42 affects MMP9
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USP42 increases the amount of MMP9. 1 / 1
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As shown in XREF_FIG, silencing of USP42 downregulated the expression of MMP-2 and MMP-9.
USP42 affects MMP2
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USP42 increases the amount of MMP2. 1 / 1
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As shown in XREF_FIG, silencing of USP42 downregulated the expression of MMP-2 and MMP-9.
USP42 affects Histone_H2B
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Results : USP42 targets histone H2B at promoters, leading to decreased ubiquitylation.
USP42 affects Histone
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USP42 activates Histone. 1 / 1
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The binding of USP42 to histone H2B suggested that USP42 may target histones for deubiquitylation.
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We conclude that USP42 inhibits Wnt signalling in HCT116 cells by destabilising the Wnt receptors , independently of its roles in p53 response to genotoxic stress .
USP42 affects FZD
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USP42 activates FZD. 1 / 1
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Accordingly, USP42 increases the turnover of LRP6 and Frizzled (FZD) receptors and inhibits Wnt signalling.
USP42 affects ENOPH1
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USP42 increases the amount of ENOPH1. 1 / 1
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USP42 knockdown significantly reduced the expression of Cyclin D1, Cyclin E1 and PCNA (XREF_FIG).
USP42 affects Cyclin
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USP42 increases the amount of Cyclin. 1 / 1
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USP42 knockdown significantly reduced the expression of Cyclin D1, Cyclin E1 and PCNA (XREF_FIG).
USP42 affects CTNNB1
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USP42 decreases the amount of CTNNB1. 1 / 1
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Transfection of USP42 siRNA significantly reduced the expression levels of beta-catenin, Twist and Snail1, while increasing E-cadherin.
USP42 affects CDKN1A
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USP42 increases the amount of CDKN1A. 1 / 1
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As we had demonstrated before, USP42 knockdown lowers p21 transcription at the early time points of p53 induction as a reflection of the reduced levels of p53.
USP42 affects CDH1
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USP42 decreases the amount of CDH1. 1 / 1
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In gastric cancer cells, USP42 is regarded as an invasion promotor since the evidence showed that silencing of USP42 upregulated the expression of the E-cadherin, and downregulated the expression of MMPs, beta-catenin, Twist, and Snail1.
Tobacco Smoke Pollution increases the amount of USP42. 1 / 1
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Organic Chemicals decreases the amount of USP42. 1 / 1
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NUP214 affects USP42
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NUP214 increases the amount of USP42. 1 / 1
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These findings establish that DENV-NS5 protein can potentially modulate the host deubiquitinase protein USP42 expression via altering cellular miR-590 levels in human microglial cells.
Histone_H2B affects USP42
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Results : USP42 targets histone H2B at promoters, leading to decreased ubiquitylation.
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4,4'-sulfonyldiphenol decreases the amount of USP42. 1 / 1
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