USP35 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 35
HGNC Gene Symbol
USP35
Identifiers
hgnc:20061 NCBIGene:57558 uniprot:Q9P2H5
Orthologs
mgi:2685339 rgd:1565984
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP35
Number of Papers
20 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
TIGD3 tigger transposable element derived 3 0.266
RASGRP2 RAS guanyl releasing protein 2 0.238
HSPB6 heat shock protein family B (small) member 6 0.227
AHNAK AHNAK nucleoprotein 0.221
MS4A15 membrane spanning 4-domains A15 0.209
TENT5A terminal nucleotidyltransferase 5A 0.205
SYT12 synaptotagmin 12 0.203

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP35using 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:0071277 cellular response to calcium ion Biological Process 1.10e-04 1.08e-02 4.06e-03
GO:0051592 response to calcium ion Biological Process 3.64e-04 3.56e-02 6.70e-03

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP35 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
USP35 deubiquitinates TNIP2. 5 / 5
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USP35 deubiquitinates and stabilizes ABIN-2 protein.

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Collectively, our data indicated that miR let-7a-regulated USP35 can inhibit NF-kappaB activation by deubiquitination and stabilization of ABIN-2 protein and eventually inhibit cell proliferation.

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Together, these data illustrated that USP35 could up-regulate the expression of ABIN-2 by promoting ABIN-2 deubiquitination and decreasing its proteasomal degradation.

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These data illustrated that USP35 could promote ABIN-2 deubiquitination and decrease its proteasomal degradation.

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Subsequently, we presented a serial evidence to show that USP35 could deubiquitinate and stabilize ABIN-2 in cancer cells.
USP35 deubiquitinates PRKN. 1 / 1
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Reciprocally, the dequbiquitination enzymes USP30 and USP35 have been shown to antagonize the mitophagy process by deubiquitinating Parkin [138,139].
USP35 deubiquitinates STING1. 1 / 1
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Our data further showed that USP35 can directly deubiquitinate and inactivate STING.
USP35 deubiquitinates AURKB. 1 / 1
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Recently, we have found that USP35 acts as a deubiquitinating enzyme (DUB) for Aurora B and affects its stability during cell division, thus being involved in the regulation of mitosis.
Modified USP35 leads to the deubiquitination of TNIP2. 1 / 1
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Immunoprecipitation with Flag-ABIN-2 followed by HA-Ub immunoblotting showed overexpression of USP35 dramatically decreased the ABIN-2 ubiquitination.
USP35 deubiquitinates VDAC1. 1 / 1
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USP35 leads to the deubiquitination of ESR1. 1 / 1
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Mechanistically, USP35 enhanced ERalpha stability by interacting and deubiquitinating ERalpha, and transcriptional activity of ERalpha by interacting with ERalpha in DNA regions containing estrogen response element.
USP35 leads to the deubiquitination of BIRC5. 1 / 1
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USP35 interacted with and promoted the deubiquitination of the survivin protein.

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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USP35 inhibits cancer cell proliferation.

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Liu and colleagues have reported that USP35 inhibits cell proliferation via suppression of NF-κB activation by deubiquitination and stabilization of ABIN-2 (Liu C et al (2015) Oncotarget 6, 27891–27906).

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Taking together, these results suggested that USP35 is an inhibitor of proliferation in cancer cells both in vitro and in vivo.

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We then determined the roles of USP35 and found that overexpression of USP35 could inhibit cancer cell proliferation in vitro and tumorigenesis in vivo.

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Ectopic USP35 expression in cancer cells inhibited cell proliferation, while silencing USP35 induced proliferation in vitro.

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USP35 overexpression inhibited cell proliferation in vitro and inhibited xenograft tumor growth in vivo.

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USP35 inhibits cancer cell proliferation.

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USP35 activated by miR let-7a inhibits cell proliferation and NF-kappaB activation through stabilization of ABIN-2.

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MTT results showed that overexpression of USP35 inhibited cell proliferation significantly compared with their respective controls in both H1299 and LNCaP cells (Figure xref ).

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MTT results showed that overexpression of USP35 inhibited cell proliferation significantly compared with their respective controls in both H1299 and LNCaP cells.

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Ectopic USP35 expression in cancer cells inhibited cell proliferation, while silencing USP35 induced proliferation in vitro.
USP35 affects TNIP2
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USP35 activates TNIP2.
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USP35 activates TNIP2. 2 / 4
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The results showed that overexpression of USP35 significantly extended the half-life of ABIN-2, while silenced expression of USP35 shortened the half-life of ABIN-2, indicating that USP35 promotes ABIN-2 protein stabilization.

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Furthermore, USP35 can increase the activity of ABIN-2 by stabilizing its protein.
USP35 increases the amount of TNIP2.
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Modified USP35 increases the amount of TNIP2. 1 / 1
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The following Western blot analysis showed that USP35 overexpression increased ABIN-2 expression while USP35 knockdown decreased its expression.
USP35 increases the amount of TNIP2. 1 / 1
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Together, these data illustrated that USP35 could up-regulate the expression of ABIN-2 by promoting ABIN-2 deubiquitination and decreasing its proteasomal degradation.
USP35 decreases the amount of TNIP2.
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USP35 decreases the amount of TNIP2. 1 / 1
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Meanwhile, proteasome inhibition caused a significant increase in ABIN-2 protein level and blocked the USP35 induced different expression of ABIN-2.
USP35 affects NFkappaB
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Functionally, both ABIN-2 and USP35 could inhibit TNFα-induced NF-κB activation and overexpression of ABIN-2 alleviated USP35-loss induced activation of NF-κB. Collectively, our data indicated that miR let-7a-regulated USP35 can inhibit NF-κB activation by deubiquitination and stabilization of ABIN-2 protein and eventually inhibit cell proliferation.

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USP35 activated by miR let-7a inhibits cell proliferation and NF-kappaB activation through stabilization of ABIN-2.

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XREF_BIBR In addition, miR-let-7a was shown to regulate USP35 expression, which then inhibited NF-kappaB activation by deubiquitination and stabilization of TNIP2 protein.

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Collectively, our data indicated that miR let-7a-regulated USP35 can inhibit NF-kappaB activation by deubiquitination and stabilization of ABIN-2 protein and eventually inhibit cell proliferation.
MARCHF8 affects USP35
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MARCHF8 activates USP35.
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MARCHF8 activates USP35. 4 / 4
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These findings indicate that USP35 up-regulated by miR let-7a potentially functions as a tumor suppressor and inhibits tumor growth.

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The molecular pathways by which miR let-7a up-regulates USP35 need to be further investigated.

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In the present study, we first identified USP35, a member of the USP superfamily, can be up-regulated by the miR let-7a.

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USP35 activated by miR let-7a inhibits cell proliferation and NF-kappaB activation through stabilization of ABIN-2.
MARCHF8 increases the amount of USP35.
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MARCHF8 increases the amount of USP35. 2 / 2
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Although, USP35 is not a predicted target of miR let-7a by the web based bioinformatic analysis, the fact from our experiment is that the expression of USP35 can be up-regulated by miR let-7a.

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MiR let-7a up-regulates the expression of USP35.
USP35 affects USP35
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USP35 decreases the amount of USP35. 1 / 3
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The USP35 level was decreased by USP35 siRNA while toxicity by siRNA transfection in the cells was not observed.
Modified USP35 decreases the amount of USP35. 1 / 1
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The results showed that miR let-7a mimics increased USP35 expression and its inhibitor decreased USP35 expression.
USP35 affects PRKN
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USP35 inhibits PRKN. 2 / 3
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Parkin mediated effects are further regulated by de-ubiquitinating enzymes, such as USP30 and USP35, which reportedly de-ubiquitinate Parkin substrates to antagonize mitophagy [24 *] or Parkin depende[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Parkin mediated effects are further regulated by de-ubiquitinating enzymes, such as USP30 and USP35, which reportedly de-ubiquitinate Parkin substrates to antagonize mitophagy [XREF_BIBR] or Parkin dependent cell death [XREF_BIBR].
USP35 affects cell growth
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So we speculate that USP35 can inhibit cancer cell growth through inhibiting NF-kappaB pathway by stabilizing ABIN-2.

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These results suggest that USP35 can inhibit cancer cell growth efficiently.
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USP35 iso2 led to ER stress, BAP31 cleavage and activation of caspase-8 and caspase-3, resulting in apoptosis [74] .

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USP35 iso2 led to ER stress, BAP31 cleavage and activation of caspase-8 and caspase-3, resulting in apoptosis [XREF_BIBR].
FOXM1 affects USP35
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FOXM1 increases the amount of USP35. 2 / 2
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In addition, the mRNA and protein levels of both USP35 and Aurora B were increased by FoxM1 in a dose dependent manner.

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Finally, the transcription factor FoxM1 promotes the expression of USP35, as well as that of Aurora B, during the cell cycle.
USP35 affects Histone_H3
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USP35 increases the amount of Histone_H3.
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USP35 increases the amount of Histone_H3. 1 / 1
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However, phospho-histone H3 levels were decreased by USP35 knockdown regardless of whether MG132 was present or not.
USP35 decreases the amount of Histone_H3.
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USP35 decreases the amount of Histone_H3. 1 / 1
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Western blot analysis also showed that the depletion of USP35 lowered the levels of both phospho-histone H3 and Aurora B protein in nocodazole treated cells.

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No evidence text available
Sunitinib affects USP35
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Sunitinib decreases the amount of USP35. 1 / 1
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No evidence text available
Quercetin affects USP35
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Quercetin increases the amount of USP35. 1 / 1
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No evidence text available
Paracetamol affects USP35
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Paracetamol decreases the amount of USP35. 1 / 1
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No evidence text available
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Methamphetamine decreases the amount of USP35. 1 / 1
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No evidence text available
Leflunomide affects USP35
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Leflunomide decreases the amount of USP35. 1 / 1
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No evidence text available
Jinfukang affects USP35
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Jinfukang increases the amount of USP35. 1 / 1
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No evidence text available
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Hsa-miR-127-3p decreases the amount of USP35. 1 / 1
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biopax:mirtarbase
No evidence text available
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Hsa-let-7a-5p decreases the amount of USP35. 1 / 1
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biopax:mirtarbase
No evidence text available
Hexabromocyclododecane decreases the amount of USP35. 1 / 1
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No evidence text available
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Cyclosporin A increases the amount of USP35. 1 / 1
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No evidence text available
Copper(II) sulfate increases the amount of USP35. 1 / 1
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No evidence text available
Cisplatin affects USP35
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Cisplatin increases the amount of USP35. 1 / 1
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No evidence text available
Bisphenol A affects USP35
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Bisphenol A decreases the amount of USP35. 1 / 1
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No evidence text available
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Benzo[a]pyrene increases the amount of USP35. 1 / 1
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No evidence text available
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Azathioprine increases the amount of USP35. 1 / 1
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No evidence text available
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Aluminium atom decreases the amount of USP35. 1 / 1
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No evidence text available
Abrine affects USP35
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Abrine decreases the amount of USP35. 1 / 1
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No evidence text available
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Since it is known that the ubiquitination of Aurora B regulates its stability or localization XREF_BIBR, XREF_BIBR, we then tested whether USP35 could perturb the protein levels or localization of Aurora B.
USP35 affects cytokinesis
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We wanted to delineate the molecular mechanism by which the depletion of USP35 increases the frequency of mitotic defects and cytokinesis failures.
USP35 affects cell death
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Parkin mediated effects are further regulated by de-ubiquitinating enzymes, such as USP30 and USP35, which reportedly de-ubiquitinate Parkin substrates to antagonize mitophagy [24 *] or Parkin depende[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP35 affects TNFRSF10B
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USP35 iso2 upregulated C/EBP homologous protein (CHOP) and DR5 in U2OSFIpIn and HeLa FIpIn cells [74] .
USP35 affects STING1
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USP35 inhibits STING1. 1 / 1
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Our data further showed that USP35 can directly deubiquitinate and inactivate STING.

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USP35 iso2 led to ER stress, BAP31 cleavage and activation of caspase-8 and caspase-3, resulting in apoptosis [74] .
USP35 affects ESR1
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USP35 activates ESR1. 1 / 1
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USP35, regulated by estrogen and AKT, promotes breast tumorigenesis by stabilizing and enhancing transcriptional activity of estrogen receptor alpha.
USP35 affects DDIT3
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USP35 activates DDIT3. 1 / 1
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USP35 iso2 upregulated C/EBP homologous protein (CHOP) and DR5 in U2OSFIpIn and HeLa FIpIn cells [74] .
USP35 affects CEBP
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USP35 activates CEBP. 1 / 1
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USP35 iso2 upregulated C/EBP homologous protein (CHOP) and DR5 in U2OSFIpIn and HeLa FIpIn cells [74] .
USP35 affects CDH1
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USP35 inhibits CDH1. 1 / 1
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USP35 inhibits CDH1 mediated degradation of Aurora B. Having noted the effect of USP35 depletion on the levels of Aurora B protein, we expected that USP35 could deubiquitinate Aurora B, and counteract the ubiquitination activity of APC CDH1 E3 ligase.
Soman affects USP35
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Soman decreases the amount of USP35. 1 / 1
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No evidence text available
USP35 is modified
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USP35 is degraded. 1 / 1
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The results showed that miR let-7a mimics increased USP35 expression and its inhibitor decreased USP35 expression.
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No evidence text available
17alpha-ethynylestradiol increases the amount of USP35. 1 / 1
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Estrogen enhanced USP35 protein levels by downregulating USP35 targeting miRNA-140-3p and miRNA-26a-5p.
1,3-dinitrobenzene decreases the amount of USP35. 1 / 1
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No evidence text available
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No evidence text available