UCHL5 Data Analysis

HGNC Gene Name: ubiquitin C-terminal hydrolase L5
HGNC Gene Symbol: UCHL5
Identifiers: hgnc:19678 NCBIGene:51377 uniprot:Q9Y5K5
Orthologs: mgi:1914848 rgd:1305414
INDRA Statements: deubiquitinations all statements
Pathway Commons: Search for UCHL5
Number of Papers: 181 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)
NFRKB	nuclear factor related to kappaB binding protein	0.535	BioGRID IntAct INDRA (11) Reactome (4)	0.06	0.26	4.20e-01
TFPT	TCF3 fusion partner	0.452	BioGRID IntAct INDRA (1) Reactome (4)	0.21	1.07	3.01e-03
INO80	INO80 complex ATPase subunit	0.425	BioGRID IntAct INDRA (5) Reactome (4)	-0.15	-0.89	5.10e-02
INO80E	INO80 complex subunit E	0.379	BioGRID IntAct NURSA INDRA (1) Reactome (4)	0.16	0.81	2.08e-02
TBRG1	transforming growth factor beta regulator 1	0.341		-0.01	-0.16	9.23e-01
INO80B	INO80 complex subunit B	0.341	BioGRID IntAct INDRA (1) Reactome (4)	-0.01	-0.17	8.83e-01
ACTR8	actin related protein 8	0.294	BioGRID IntAct INDRA (1) Reactome (4)	-0.00	-0.11	9.65e-01

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with UCHL5using 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:0033202	DNA helicase complex	Cellular Component	5.41e-19	4.16e-17	2.33e-17
GO:0097346	INO80-type complex	Cellular Component	1.45e-17	1.12e-15	3.14e-16
GO:0070603	SWI/SNF superfamily-type complex	Cellular Component	2.36e-14	1.81e-12	3.39e-13
GO:1904949	ATPase complex	Cellular Component	1.45e-13	1.12e-11	1.56e-12
GO:0006310	DNA recombination	Biological Process	6.77e-11	5.21e-09	5.84e-10
GO:0070646	protein modification by small protein removal	Biological Process	1.01e-10	7.75e-09	7.24e-10
GO:0000790	nuclear chromatin	Cellular Component	3.64e-10	2.80e-08	2.24e-09
GO:0006338	chromatin remodeling	Biological Process	2.18e-07	1.68e-05	1.18e-06

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out UCHL5 using CRISPR-Cas9.

Knockout Differential Expression

Symbol	Name	log₂-fold-change	p-value	p-value (adj.)
RPS28	ribosomal protein S28	1.11e+00	1.06e-07	1.17e-03
RPS9	ribosomal protein S9	1.27e+00	7.81e-08	1.17e-03
IGFBP4	insulin like growth factor binding protein 4	-4.19e-01	2.91e-06	2.14e-02

Gene Set Enrichment Analysis

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

Literature Mining

INDRA was used to automatically assemble known mechanisms related to UCHL5 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

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UCHL5 deubiquitinates SMAD2. 5 / 5

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In the present study, we demonstrate that UCHL5 de-ubiquitinates and stabilizes Smad2 and Smad3, thereby promoting TGFbeta-1 signaling.

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Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases

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Here, we demonstrate that UCHL5 de-ubiquitinates and stabilizes Smad2 and Smad3, thereby promoting TGFbeta-1 signaling and contributes to the pathogenesis of pulmonary fibrosis.

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Also, OTUB1 regulates only phosphorylated Smad2 and Smad3 under TGFbeta-1 treatment XREF_BIBR, while UCHL5 de-ubiquitinates Smad2 and Smad3 regardless of TGFbeta-1 treatment.

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UCHL5 deubiquitinates TGFBR1. 5 / 5

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One such DUB is UCH37, which was shown to bind to Smad7 and deubiquitinate TbetaRI.

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Via SMAD7, UCH37 can further be recruited to TβRI, where it removes polyubiquitin chains synthesized by SMURF

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XREF_BIBR reported that UCHL5 de-ubiquitinates and stabilizes TbetaRI in human cancer cells.

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It has been revealed that the DUBs, UCH37, USP11, and USP15, de-ubiquitinate and stabilize TbetaRI.

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Similarly to USP15, another deubiquitylating enzyme, UCH37, forms a complex with Smad7 by binding to a sequence that is distinct from the PY motif with which Smurf1 or Smurf2 interact, and also deubiquitylates and stabilizes TbetaRI.

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UCHL5 deubiquitinates SMAD3. 4 / 4

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In the present study, we demonstrate that UCHL5 de-ubiquitinates and stabilizes Smad2 and Smad3, thereby promoting TGFbeta-1 signaling.

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Also, OTUB1 regulates only phosphorylated Smad2 and Smad3 under TGFbeta-1 treatment XREF_BIBR, while UCHL5 de-ubiquitinates Smad2 and Smad3 regardless of TGFbeta-1 treatment.

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Here, we demonstrate that UCHL5 de-ubiquitinates and stabilizes Smad2 and Smad3, thereby promoting TGFbeta-1 signaling and contributes to the pathogenesis of pulmonary fibrosis.

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UCHL5 deubiquitinates E2F1. 4 / 4

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Here we identify UCH37 as the first, to our knowledge, deubiquitinating enzyme for E2F1.

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In addition, Uch37 deubiquitinates E2 promoter binding factor 1 (E2F1), promoting transcription of pro apoptotic and cell cycle related genes XREF_BIBR.

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Instead, UCH37, but not a catalytically dead mutant, decreases the Lys-63-linked ubiquitination of E2F1 and activates its transcriptional activity.

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UCHL5 activates the E2F1 transcriptional activity by decreasing Lys-63-linked ubiquitination of E2F1.

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UCHL5 deubiquitinates TCF7. 4 / 4

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However, deubiquitination of TCF7 by UCH37 is involved in TCF7 binding to the promoters of c-Myc, and Cyclin D1 [XREF_BIBR, XREF_BIBR].

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Because Uch37 mediates deubiquitination of Tcf7 protein without affecting its stability, we next sought to elucidate the non proteolytic role of Uch37 mediated deubiquitination of Tcf7 and subsequent activation of Wnt signalling.

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Here, we report that Uch37 mediates the deubiquitination of Tcf7 without affecting protein stability.

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To further examine if Uch37 directly deubiquitinates Tcf7, we conducted in vitro deubiquitination assays using immunopurified Tcf7-ubiquitin conjugates.

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UCHL5 deubiquitinates TGFB. 3 / 3

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Wicks et al. reported that UCH37 can deubiquitinate and stabilize type I TGFbeta receptor and augment TGFbeta signaling [XREF_BIBR] (XREF_FIG).

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In addition, we show that UCH37 can deubiquitinate and stabilize the type I TGF-beta receptor.

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The study hypothesized that Smad7 could act as an adaptor to recruit UCH37 to the type I TGF-beta receptor and showed that UCH37 dramatically up-regulates TGF-beta-dependent gene expression by deubiquitinating and stabilizing the type I TGF-beta receptor [XREF_BIBR].

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UCHL5 deubiquitinates NLRP3. 3 / 3

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Deubiquitination of NLRP3 by UCHL5 is required for inflammasome activation.

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Rv1579c, secreted from MTB H37Rv RD3, interacts with the receptor for activated C kinase 1 (RACK1) via its amino acid Y80 at the C-terminus, then recruits ubiquitin C-terminal hydrolase L5 (UCHL5) to deubiquitinate NLRP3, and finally activate the NLRP3 inflammasome [XREF_BIBR].

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Deubiquitination and Activation of the NLRP3 Inflammasome by UCHL5 in HCV-Infected Cells.

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UCHL5 leads to the deubiquitination of NFRKB. 3 / 3

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LncRNA DRAIC inhibits proliferation and metastasis of gastric cancer cells through interfering with NFRKB deubiquitination mediated by UCHL5.

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Combining the above results, it can be concluded that DRAIC mediates the ubiquitylation degradation of NFRKB by interfering with deubiquitination of NFRKB induced by UCHL5, and then exerts an anti-cancer effect in GC.

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So we further tested the ubiquitination level of NFRKB, and found that the NFRKB ubiquitination level increased significantly after oeDRAIC, which could demonstrate that DRAIC weakens the deubiquitination of NFRKB mediated by UCHL5, and maintains the ubiquitination level of NFRKB and boost the degradation of NFRKB via the ubiquitination-proteasome pathway.

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UCHL5 deubiquitinates SMO. 2 / 2

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The deubiquitinase UCHL5/UCH37 positively regulates Hedgehog signaling by deubiquitinating Smoothened

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We provide both genetic and biochemical evidence that UCHL5 interacts with and deubiquitinates Smo, increasing stability and promoting accumulation at the cell membrane.

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UCHL5 deubiquitinates SMAD7. 2 / 2

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Type 1 TGF-beta receptor (TGF-betaR1) is degraded by Smad7 dependent ubiquitination-proteasomal pathway, which is deubiquitinated by ubiquitin C-terminal hydrolase-L5 (UCHL5).

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Type I TGF-beta receptor (TGF-betaR I) is degraded by Smad7 dependent ubiquitination-proteasomal pathway, which is deubiquitinated by ubiquitin C-terminal hydrolase-L5 (UCHL5).

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UCHL5 deubiquitinates TGFBR. 2 / 2

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In addition, we show that UCH37 can deubiquitinate and stabilize the type I TGF-beta receptor.

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UCHL5 deubiquitinates NOS2. 1 / 1

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In this study, we show that Rpn13 is involved in iNOS degradation and is required for iNOS interaction with the deubiquitination protein UCH37.

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Modified UCHL5 leads to the deubiquitination of SMAD2. 1 / 1

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We demonstrate that Smad2 and Smad3 ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5.

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UCHL5 deubiquitinates Proteasome on S26. 1 / 1

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Thus Uch37 and Usp14 may both deubiquitinate the 26S proteasome.

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UCHL5 deubiquitinates TCF3. 1 / 1

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It was reported that UCHL5 deubiquitinates Tcf3, which helps it to fully activate the Wnt/β–catenin pathway [143].

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UCHL5 deubiquitinates PRPF19. 1 / 1

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Ubiquitin C-terminal Hydrolase 37, a novel predictor for hepatocellular carcinoma recurrence, promotes cell migration and invasion via interacting and deubiquitinating PRP19.

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UCHL5 deubiquitinates signaling receptor activity. 1 / 1

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In addition, we show that UCH37 can deubiquitinate and stabilize the type I TGF-beta receptor.

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UCHL5 leads to the deubiquitination of NLRP3 on K48. 1 / 1

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S3E), suggesting that UCHL5 mediates K48 deubiquitination of NLRP3 after EST12 stimulation.

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Modified UCHL5 leads to the deubiquitination of SMAD3. 1 / 1

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We demonstrate that Smad2 and Smad3 ubiquitination was diminished by over-expression of UCHL5, while it was enhanced by inhibition or down-regulation of UCHL5.

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UCHL5 deubiquitinates TGFBR on R1. 1 / 1

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UCHL5 can deubiquitinate and stabilize Smads as well as TGF-beta receptor 1 (TGF-beta R1) and therefore activate TGF-beta signaling [XREF_BIBR].

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UCHL5 deubiquitinates NFKBIA. 1 / 1

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Furthermore, we discovered that IkappaB-alpha, a protein whose proteasomal degradation activates the transcription factor NF-kappaB, is also a substrate for the Rpn13/UCH37 complex.

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UCHL5 deubiquitinates Proteasome. 1 / 1

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Another proposal is that UCH37 deubiquitylates proteasome subunits that can undergo regulatory ubiquitylation.

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UCHL5 deubiquitinates TGFB on R1. 1 / 1

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UCHL5 can deubiquitinate and stabilize Smads as well as TGF-beta receptor 1 (TGF-beta R1) and therefore activate TGF-beta signaling [XREF_BIBR].

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Other Statements

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ADRM1 affects UCHL5

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ADRM1 activates UCHL5.

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ADRM1 activates UCHL5. 10 / 60

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Consistent with our previous report that hRpn13 activates Uch37, the Uch37-hRpn13 complex reacts with UbVS more rapidly than Uch37 alone ( Figure 3 A).

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Thus, hRpn13 activates hINO80-associated Uch37 without displacing it from the hINO80 complex, and activation is a consequence of transient interactions between Uch37 and hRpn13.

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A mechanism for the activation of Uch37 by Rpn13 is discussed.

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We further demonstrated that the carboxyl-terminal tail of Uch37 is auto-inhibitory and that hRpn13 activates the Uch37 deubiquitinating activity through interactions with this tail domain.

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Interestingly, addition of exogenous recombinant hRpn13 to hINO80 caused a marked activation of Uch37, both in UbAMC hydrolysis and in UbVS reactivity (XREF_FIG).

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However, this mutant was only marginally activated by the addition of RPN13 DEU (2.7-fold instead of 7-fold in WT), indicating that UCH-L5 activation by RPN13 DEU requires an intact CL ( xref F; xref and xref ).

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Stimulation of deubiquitylating activity can now be added to this list of proteasomal functions, but neither ATPase nor proteolytic function of the proteasome is required, as Rpn13 alone can activate Uch37.

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For example, it is not clear how hRpn13 activates Uch37, but it is possible that its strong ubiquitin-binding affinity contributes by increasing Uch37’s affinity for its substrates when in the hRpn13 complex and by helping to orient neighboring ubiquitin moieties in a configuration that is optimal for hydrolysis.

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Their interaction with ubiquitin is not essential for RPN13 activation of UCH37 for ubiquitin-AMC, as their mutation to alanine produced a 2.5-fold reduction ( xref ) or negligible effect ( xref ); wild-type RPN13 increases this activity 8-fold ( xref ; xref ).

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It has been proved that UCH37 can be activated by proteasome ubiqutin chain receptor Rpn13 and incorporation into the 19S complex.

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ADRM1 inhibits UCHL5.

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ADRM1 inhibits UCHL5. 1 / 6

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We propose that RA190 targets hRpn13 and Uch37 through parallel mechanisms and at proteasomes, RA190 inactivated Uch37 can not disassemble hRpn13 bound ubiquitin chains.

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ADRM1 increases the amount of UCHL5.

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ADRM1 increases the amount of UCHL5. 1 / 1

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Intriguingly, hRpn13 knockdown leads to reduced levels of Uch37 in cells XREF_BIBR XREF_BIBR and similar phenotypes are observed by hRpn13 or Uch37 knockdown XREF_BIBR; however, the mechanism linking hRpn13 to Uch37 protein levels remain unknown.

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ADRM1 deubiquitinates UCHL5.

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ADRM1 deubiquitinates UCHL5. 1 / 1

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HRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5.

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RPN13 affects UCHL5

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RPN13 activates UCHL5.

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RPN13 activates UCHL5. 10 / 25

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Here we show how the DEUBAD domain in RPN13 activates UCH-L5 by positioning its C-terminal ULD domain and crossover loop to promote substrate binding and catalysis.

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In line with previous data, we found that the DEUBAD domain of RPN13 activates UCH-L5 (UR).

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As discussed below, the differences in UCH domain contacts and the attendant orientations of the CTD helices explain the activation of UCH37 by RPN13 and its inhibition by NFRKB.

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Therefore, it appears that Rpn13 can transiently activate Uch37 in a " hit-and-run " manner without disrupting its association with INO80.

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We show how the DEUBAD domain in RPN13 activates UCH-L5 by tuning the conformation of structural elements in UCH-L5, and inhibits in INO80G, where it exploits molecular mimicry and UCH-L5 conformational plasticity to prevent ubiquitin docking and catalysis.

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RPN13 can activate UCH37 by disrupting dimerization, although physiologically-relevant activation likely results from stabilization of a surface competent for ubiquitin binding and modulation of the active-site crossover loop.

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That Uch37 binds and is activated by Rpn13 raises the potential for its selective activity on substrates docked via Rpn13.

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Rpn13 activated Uch37 by forming a 1:1 stoichiometric complex in which the active site of Uch37 was accessible to Ub.

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However, the mechanism by which Rpn13 activates Uch37 is not known.

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RPN13 bound to UCHL5 activates UCHL5. 2 / 2

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Rpn13 can interact with Uch37 and recruit it to the proteasome via its C-terminal 46 residues (also called the KEKE motif) and activates Uch37.

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Binding of Rpn13 to Uch37 increases the isopeptidase activity of Uch37; therefore it may facilitate the rescue of ubiquitinated substrates from proteolysis XREF_BIBR, XREF_BIBR, XREF_BIBR.

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RPN13 inhibits UCHL5.

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RPN13 inhibits UCHL5. 3 / 3

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The deubiquitinating enzyme UCH-L5 can be inhibited and activated by regulatory proteins INO80G and RPN13, respectively.

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RPN13 disrupts a UCH37 dimer at high concentration.

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Using a combination of mutagenesis, biochemical, and small-angle X-ray scattering (SAXS) techniques, we demonstrated that Rpn13 activated the auto-inhibited Uch37 by de-oligomerizing it and sequestering it to form a 1:1 stoichiometric complex.

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RPN13 increases the amount of UCHL5.

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Modified RPN13 increases the amount of UCHL5. 1 / 1

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Loss of Rpn13 caused concurrent loss of Uch37, a deubiquitinating enzyme bound to Rpn13, consistent with our previous work [XREF_BIBR].

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RPN13 deubiquitinates UCHL5.

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RPN13 deubiquitinates UCHL5. 1 / 1

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RP ubiquitin receptors S5a and Rpn10 and Rpn13 capture substrates by recognizing their covalently attached ubiquitin chains, which are removed and disassembled by three deubiquitinating enzymes Rpn11, Ubp6 and Usp14 and Uch37 and UCHL5.

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NFRKB affects UCHL5

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NFRKB inhibits UCHL5.

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NFRKB inhibits UCHL5. 10 / 14

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The deubiquitinating enzyme UCH-L5 can be inhibited and activated by regulatory proteins INO80G and RPN13, respectively.

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In contrast, NFRKB inhibits UCH37 by blocking the ubiquitin-binding site and by disrupting the enzyme active site.

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Our binding assays showed that INO80G DEU decreases the affinity of UCH-L5 for substrates (XREF_FIG A and 2B).

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The related DEUBAD domain in INO80G inhibits UCH-L5 by exploiting similar structural elements in UCH-L5 to promote a radically different conformation, and employs molecular mimicry to block ubiquitin docking.

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NFRKB NTD inhibits UCH37 because of two distinct contacts that it makes with the UCH domain.

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Surprisingly, the truncated protein INO80G DEU Deltaalpha6 still inhibited UCH-L5 (XREF_FIG B), demonstrating that helix alpha6 is not required for inhibition under these conditions.

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Analysis of the UCH-L5 and INO80G DEU interface shows how the large conformational changes in UCH-L5 organize novel interfaces where key elements for ubiquitin binding and RPN13 DEU -mediated activation are exploited by INO80G DEU to inhibit UCH-L5 activity.

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Uch37 activity can be inhibited by NFRKB alone or by incorporation into hINO80.

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Inhibition of UCH37 by NFRKB NTD.

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Mechanism of UCH-L5 Inhibition by INO80G DEU .

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NFRKB activates UCHL5.

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NFRKB activates UCHL5. 8 / 8

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Why does NFRKB DEU fail to activate Uch37?

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To determine whether NFRKB also modulates Uch37 activity, we affinity purified from insect cells recombinant Uch37 in complexes with NFRKB, various NFRKB derivatives, or hRpn13 and assayed Uch37 for i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Enzyme kinetics analysis confirmed that INO80G short activates UCH-L5 on Ub-AMC (XREF_FIG B).

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To determine whether NFRKB also modulates Uch37 activity, we affinity purified from insect cells recombinant Uch37 in complexes with NFRKB, various NFRKB derivatives, or hRpn13 (XREF_SUPPLEMENTARY) and assayed Uch37 for its ability to react with ubiquitin vinylsulfone (UbVS).

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INO80G short, containing only the helices alpha2-alpha4 of the DEUBAD domain, can activate UCH-L5, demonstrating that the core DEUBAD fold is already sufficient to bind and provide modest activation.

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Our data show how UCH-L5 activity can be modulated by DEUBAD domains present in RPN13 and INO80G through remarkably large conformational changes.

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Our observations are consistent with the findings that RPN13 competes with NFRKB 1-101 for binding to UCH37 and that NFRKB residues 1-101 activate UCH37 but that the longer full-length and 1-465 constructs inhibit UCH37, as do the 39-156 and 1-117 constructs used in this study.

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Intriguingly, an artificial shorter version of INO80G was found to activate UCH-L5 invitro.

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UCHL5 affects Neoplasm Invasiveness

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UCHL5 activates Neoplasm Invasiveness.

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UCHL5 activates Neoplasm Invasiveness. 10 / 11

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A high UCHL5 expression level predicts early recurrence and promotes cell migration and invasion in hepatocellular carcinoma (HCC) XREF_BIBR.

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UCHL5 is also overexpressed in hepatocellular carcinoma, and was shown to promote cell migration and invasion 57 .

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We believe that UCH37 could be a good diagnostic and therapeutic target for controlling HCC recurrence, and further investigations in this field are needed.This study provided evidence for the first t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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A high UCHL5 expression level predicts early recurrence and promotes cell migration and invasion in hepatocellular carcinoma ( HCC ) 12 .

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In vitro, we discovered that UCH37 could promote cell migration and invasion.

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Intriguingly, knock-down of PRP19 reduced the capability of cell migration and invasion, compare with the control cells, suggesting that UCH37 exerted its effects at least in part by deubiquitinating [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Furthermore, we discovered that UCH37 could promote cell migration and invasion in HCC cell lines through interacting and deubiquitinating PRP19, an essential RNA splicing factor.Tumor specimens used [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UCH37-knockdown reduced the cell capability to invade extracellular matrix (Huh7-pLKO.1, 23 +/- 3 vs. Huh7-shUCH37, 3 +/- 1, p < 0.05), whereas forced expression of UCH37 increased invasiveness (L02-p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UCHL5 is also overexpressed in hepatocellular carcinoma , and was shown to promote cell migration and invasion 57 .

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All of the evidences suggest that the up-regulation of UCH37 may play an important role in oncogenesis through promoting some proto-oncogenes ' expression and stem cell like characteristics in the cel[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UCHL5 inhibits Neoplasm Invasiveness.

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Overexpression of UCH-L5 by Lentivirus infection inhibits migration and invasion of human glioma cells.

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In vitro, we found that UCH-L5 could inhibit migration and invasion of U87MG and U251 cells.

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In vitro analysis revealed that UCHL5 can inhibit migration and invasion of glioma cells mediated via a downregulation of SNRPF [142].

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Furthermore, we discovered that UCH-L5 could inhibit cell migration and invasion of glioma cell lines through downregulating SNRPF, a factor of Sm protein ring in the spliceosome.

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These results suggest that UCH-L5 may inhibit the migration and invasion of glioma cells to inhibit the occurrence of glioma.

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Furthermore, we found that knockdown of UCH-L5 expression promotes the migration and invasion of U87MG and U251 cells.

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And overexpression of UCH-L5 inhibits the migration and invasion of U87MG and U251 cells.

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So UCH-L5 could inhibit glioma cell migration and invasion via downregulating SNRPF.

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Our study showed that UCH-L5 could inhibit migration and invasion of glioma cells via down regulating expression of SNRPF.

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Knockdown expression of UCH-L5 by siRNA promotes migration and invasion of human glioma cells.

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UCHL5 affects Ubiquitin

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UCHL5 activates Ubiquitin.

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RPN11 and POH1 has been demonstrated to cleave at the base of the ubiquitin chain, removing ubiquitin en masse, while UCH37 and USP14 mediate a stepwise removal of ubiquitin from the substrate starting from the distal end.

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RPN11 cleaves at the base of the ubiquitin chain where it is linked to the substrate, whereas UCH37 and apparently USP14 mediate a stepwise removal of ubiquitin from the substrate by disassembling the chain from its distal tip.

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UPS14 and UCH37 are thought to mediate stepwise disassembly of the Ub chain from the distal end 6 .

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The western blot results showed that inhibition of both UCHL5 and USP14 by b-AP15 significantly increased the accumulation of polyubiquitinated proteins by 31.80 +/- 6.25% (P = 0.008, n = 5) and reduc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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RPN11 appears to cleave at the base of the ubiquitin chain, where it is linked to the substrate, whereas USP14 and UCHL5 are known to mediate stepwise removal of ubiquitin from the substrate by disassembling the chain from its distal end [XREF_BIBR].

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Once bound by the proteasome, deubiquitinating enzymes, like the 19S subunit Rpn11 [XREF_BIBR, XREF_BIBR] or proteasome associated Ubp6 [XREF_BIBR, XREF_BIBR] and Uch37 [XREF_BIBR, XREF_BIBR], remove the ubiquitin moiety to allow recycling of ubiquitin before degradation of the substrate.

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However, as UCHL5 and USP14 are proposed to mediate a stepwise removal of ubiquitin from the substrate by trimming the chain from its distal tip, this leaves the opportunity for MGRN1 to reach a monou[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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We, therefore, wanted to determine the type of the ubiquitin linkage targeted on Tcf7 by Uch37.

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It appears that POH1 cleaves at the base of the ubiquitin chain where it is linked to the target protein, whereas USP14 and UCHL5 mediate a stepwise removal of ubiquitin from the protein by disassembling the chain from its distal tip [XREF_BIBR].

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UCHL5 inhibits Ubiquitin.

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UCHL5 inhibits Ubiquitin. 7 / 8

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By contrast, USP14 and UCHL5 are located further from the 20S core and antagonize degradation by removing Ub in a stepwise manner from the distal end, promoting substrate dissociation from the proteasome 17.The human genome encodes for approximately 90 DUBs, which fall into six classes 18, 19.

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Since Uch37 is expected to disassemble ubiquitin chains at hRpn13 in the proteasome, we hypothesized that RA190 inactivation of Uch37 could impair the disassembly and clearance of ubiquitin chains from the proteasome.

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It has been reported that both USP14 and UCH37 prevent substrate degradation by removing ubiquitin chains and promoting proteasomal substrate dissociation.

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Mechanistically, loss of Uch37 activity at the proteasome would cause ubiquitin chains to become stalled at hRpn13 in the proteasome (XREF_FIG, right panel).

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Functional studies suggest that UCH-37 inhibits the degradation of ubiquitinated proteins by the proteasome by removing ubiquitin from the distal end of the polyubiquitin chain.

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The degradation of Ub itself is closely related to the activities of DUBs associated with the proteasome since the loss of USP14 (or Ubp6 in yeast) or UCH37 has been shown to trigger degradation of Ub along with its target substrates, leading to depletion of the free Ub pool XREF_BIBR - XREF_BIBR.

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UCHL5 affects cell migration

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UCHL5 activates cell migration.

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UCHL5 activates cell migration. 10 / 12

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Collectively, this study demonstrated that UCH37 could promote cell migration and invasion in HCC cell lines through interacting and deubiquitinating PRP19, and suggested that UCH37 could be a novel predictor for HCC recurrence after curative resection.

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UCHL5 is also overexpressed in hepatocellular carcinoma, and was shown to promote cell migration and invasion 57 .

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A high UCHL5 expression level predicts early recurrence and promotes cell migration and invasion in hepatocellular carcinoma ( HCC ) 12 .

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Yet UCH37 knockdown significantly impairs cell migration in pancreatic cancer cell lines through the abolition of the TGF-beta-induced expression of MMP-2 and PAI-1, which are thought to play a key ro[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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A high UCHL5 expression level predicts early recurrence and promotes cell migration and invasion in hepatocellular carcinoma (HCC) XREF_BIBR.

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In vitro, we discovered that UCH37 could promote cell migration and invasion.

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Fang Y et al. found UCH-L5 promotes cell migration and invasion via interacting and deubiquitinating splicing factor PRP19 in hepatocellular carcinoma [XREF_BIBR].

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UCHL5 is also overexpressed in hepatocellular carcinoma , and was shown to promote cell migration and invasion 57 .

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UCHL5 inhibits cell migration.

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UCHL5 inhibits cell migration. 1 / 1

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Furthermore, we discovered that UCH-L5 could inhibit cell migration and invasion of glioma cell lines through downregulating SNRPF, a factor of Sm protein ring in the spliceosome.

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UCHL5 affects apoptotic process

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UCHL5 inhibits apoptotic process.

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Targeted inhibition of the deubiquitinating enzymes, USP14 and UCHL5, induces proteotoxic stress and apoptosis in Waldenstrom macroglobulinaemia tumour cells.

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Along with others, we previously have been reported that inhibition of USP14 and UCHL5 of the 19S proteasome induces apoptosis.

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UCH37 depletion also decreases both cell proliferation and apoptosis induction in functional assays.

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Recently, novel small molecule inhibitors of the deubiquitylating enzymes USP14 and UCHL5 were developed to overcome bortezomib resistance and induce cell apoptosis of multiple myeloma XREF_BIBR, XREF_BIBR.

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A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance.

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Furthermore, cyclin-dependent kinase 4/6 (CDK4/6) inhibition decreased UCHL5 expression, suppressed OTX015-R cell proliferation, and induced apoptosis.

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Small molecule inhibitors of UCHL5 could induce apoptosis of multiple myeloma cells and reverse bortezomib resistance [XREF_BIBR].

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Using MTT assay, Western blot, Hoechst 33342 staining assay and flow cytometry, we found that silencing of UCH37 in A549 cells induced apoptosis.

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Pharmacologic inhibition of USP14 and UCHL5 with VLX1570 induces apoptosis in drug resistant WM cells and is associated with accumulation of high-molecular-weight polyubiquitinated protein conjugates.

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UCHL5 activates apoptotic process.

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Other studies have also found that b-AP15 inhibition of USP14 and UCHL5 triggers apoptosis in MM cell lines in a time dependent and dose dependent manner.77 Similar cytotoxic effects, as those seen with b-AP15 treatment, occur within myeloma cells when treated with an alternative DUB inhibitor, copper pyrithione.77 Targeting E1 ubiquitin activating enzyme and E3 ubiquitin ligases has synergistic activity with bortezomib on cell lines.78, 79 An inhibitor of USP7, P5091, can interfere with ubiquitin binding and overcome bortezomib resistance invitro and invivo.80 NIMA related kinase 2 (NEK2) overexpression is associated with resistance to multiple drugs and poor prognosis in MM, and NEK2 inhibitor has been shown to decrease proteasome activity.81 Further investigation into its role in Bortezomib resistance is required.

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Our recent study exemplifies the feasibility of such an approach : specifically, we showed that blockade of 19S associated DUBs USP14 and UCHL5 with a small-molecule inhibitor (bAP15 and VLX1570) induces apoptosis in MM cells and overcome bortezomib resistance, with a favorable toxicity profile.

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b-AP15 is a specific UCHL5 and USP14 inhibitor identified from a screening of small molecules that induce the lysosomal apoptosis pathway.

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UCHL5 affects TGFB

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UCHL5 activates TGFB.

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UCHL5 activates TGFB. 8 / 10

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The up-regulation of TGF-beta signaling by UCH37 could also be partly explained by the deubiquitination and stabilization of Smad3 [32,33].

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In the TGFbeta pathway, UCH37 is capable of deubiquitinating the TGFbeta Type I receptor via a complex that includes Smad7 in mammalian cells and UCH37 activity serves to promote TGFbeta signaling.

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In contrast, UCH37 demonstrated a minimal increase in CAGA-Luc activity suggesting that UCH37 may also target the TGF-beta pathway downstream of the TbetaR complex to regulate overall TGF-beta signaling (XREF_SUPPLEMENTARY).

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We show that UCH37 knockdown significantly inhibits the activity of a TGFbeta dependent gene reporter and selectively decreases levels of some TGFbeta dependent target genes, notably p21 and PAI-1, but only during the early phase of TGFbeta receptor activation.

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We have shown that UCHL5 promotes TGFbeta signaling via stabilization of Smad2 and Smad3 and may be a potential therapeutic target to block the differentiation of myofibroblasts and the expression of matrix in IPF.

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Finally, AMSH-LP and UCHL5 promote TGF-beta responses through their interaction with inhibitory I-SMADs [XREF_BIBR, XREF_BIBR].

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The DUBs USP4, USP11, USP15, and UCH37 have previously been demonstrated to modulate TGF-beta pathway activity by directly deubiquitinating the TbetaRI, resulting in increased TbetaRI stability (XREF_FIG) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR.

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The up-regulation of TGF-beta signaling by UCH37 could also be partly explained by the deubiquitination and stabilization of Smad3 [67,68].

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UCHL5 increases the amount of TGFB.

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UCHL5 increases the amount of TGFB. 2 / 2

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UCH37 knockdown inhibits transcription of TGF-beta target genes and slows lateral cell migration (Cutts et al., 2011).

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UCH37 knockdown decreases transcription of TGFbeta dependent target genes and also slows lateral cell migration XREF_BIBR.

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UCHL5 affects SMAD2

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UCHL5 activates SMAD2.

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UCHL5 activates SMAD2. 2 / 10

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UCHL5 increases the amount of SMAD2.

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Inhibition or down-regulation of UCHL5 reduced Smad2 and Smad3 levels and TGFbeta-1-induced the expression of FN and alpha-SMA in human lung fibroblast.

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UCHL5 decreases the amount of SMAD2.

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UCHL5 decreases the amount of SMAD2. 1 / 1

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UCHL5 shRNA (# 2, # 3, not # 1, # 4) diminished protein levels of Smad2 and Smad3 (XREF_FIG).

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UCHL5 affects TGFB1

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UCHL5 activates TGFB1. 4 / 10

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b-AP15, an inhibitor of UCHL5, attenuates TGFbeta-1 signaling and diminishes pulmonary fibrosis in a bleomycin induced pulmonary fibrosis model.

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All these data show that UCHL5 stabilizes Smad2 and Smad3, and promotes TGFbeta-1 signaling.

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UCHL5 stabilizes Smad2 and Smad3 and promotes TGFbeta-1 signaling.

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In this study, we reveal that b-AP15, an inhibitor of UCHL5, attenuates TGFbeta-1 signaling through inducing ubiquitination and degradation of Smad2 and Smad3.

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UCHL5 affects cell population proliferation

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UCHL5 activates cell population proliferation.

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UCHL5 knockdown in LUAD cells significantly inhibited cell proliferation and reduced the expression of key cell cycle proteins.

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UCHL5 knockdown inhibits LUAD cell proliferation via regulation of cell cycle proteins.

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UCHL5 knockdown markedly inhibited cell proliferation via regulating cell cycle proteins.

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UCHL5 knockdown by two siRNA segments significantly inhibited cell proliferation in Hela cells.

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Deletion of UCH37 also down-regulated the transcription of c-Myc, a downstream effector of beta-catenin, and inhibited cell proliferation and motility.

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UCHL5 knockdown markedly inhibited cell proliferation via regulating cell cycle proteins .

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Proteasomal deubiquitinase UCH37 inhibits degradation of beta-catenin and promotes cell proliferation and motility.

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UCH37 interacts with COPS5 to induce the ubiquitination and degradation of p53 and p21 , promoting cell proliferation .

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UCHL5 inhibits cell population proliferation.

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UCHL5 inhibits cell population proliferation. 2 / 2

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Furthermore, cyclin-dependent kinase 4/6 (CDK4/6) inhibition decreased UCHL5 expression, suppressed OTX015-R cell proliferation, and induced apoptosis.

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UCH37 depletion also decreases both cell proliferation and apoptosis induction in functional assays.

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UCHL5 affects Proteasome

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UCHL5 inhibits Proteasome.

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UCHL5 inhibits Proteasome. 4 / 5

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For elderly patients with reduced proteostasis capacity, high UCHL5 levels may further inhibit proteasome activity, thereby promoting apoptosis in cancer cells.

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UCH-L5 can suppress proteasome mediated degradation via the disassembly of distal polyubiquitin moieties.

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In particular, deubiquitinating enzymes Uch37 and Usp14, being physically associated with the proteasome, may suppress proteasome activity through deubiquitinating a subset of ubiquitinated substrates, once the substrate is docked at the proteasome.

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It is possible that excess UCHL5 expression substantially impairs proteasome activity, causing abnormal accumulation of proteasomal substrates, and harming tumor cells.

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UCHL5 activates Proteasome.

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UCHL5 activates Proteasome. 5 / 5

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In addition, the fact that UCH37 activation in the proteasome complex is reversed in the INO80 complex may imply a unique compartmental role or functional partitioning of this enzyme.

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In a more targeted approach, an active-site ubiquitin probe (HA-Ub-VMS) has been used to demonstrate that USP14/UCHL5 inhibition by a small molecule (b-AP15) inhibits the 19S proteasome in a reconstituted biochemical assay.

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The C. elegans homolog of UCHL5, UBH-4, tissue-specifically modulates proteasome activity, also affecting the health and lifespan of these animals [XREF_BIBR].

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UCHL5 can suppress proteasome degradation through disassembly of distal polyubiquitin moieties (Lam et al., 1997; Schreiner et al., 2008; Koulich et al., 2008; Jacobson et al., 2009).

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In contrast, siRNA of either UCHL5 or USP14 alone did not affect proteasome composition but did increase the rate of proteasome activity, supporting previous studies.

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Proteasome affects UCHL5

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Proteasome deubiquitinates UCHL5.

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Proteasome deubiquitinates UCHL5. 5 / 5

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B-AP15 simultaneously inhibits the proteasome associated deubiquitinating enzymes UchL5 and Usp14, whereas RA190 binds and inhibits the ubiquitin receptor subunit Rpn13 [XREF_BIBR, XREF_BIBR].

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Furthermore, direct interaction of PSMD8 has been reported with the proteasome associated deubiquitinating enzyme UCH37 (Li et al., 2001).

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Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome associated deubiquitinating enzymes (USP14 and UCHL5), XPO1 and CRM1 and AURKA.

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Recently, we reported that the proteasome associated deubiquitinating enzyme UCHL5 and Uch37 is a new prognostic marker in both rectal cancer and pancreatic ductal adenocarcinoma.

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Furthermore, since deubiquitinating enzymes associated with the proteasome are responsible for ubiquitin trimming from substrates targeted to the proteasome for degradation, and in light of growing evidence that the manner in which proteasome associated deubiquitinating enzymes, USP14 and UCH37, deubiquitinate substrates can in fact suppress and delay degradation and modulate proteasome function, we decided to next analyze the functional activity of the proteasome associated deubiquitinating enzyme USP14.

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Proteasome activates UCHL5.

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First, does proteasome activated Uch37 affect INO80 mediated nucleosome remodeling activity?

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However, only recruitment into the proteasome activates Uch37.

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Proteasome inhibits UCHL5.

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HA-UbVS pretreatment of auranofin could bind the HA tagged UbVS in the purified 26S proteasome, supporting that auranofin inhibits UCHL5 and USP14.

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Activity probe assays with either the whole 26S proteasome or the 19S regulatory particle showed that the compound blocked the reaction of both USP14 and UCHL5 with haemagglutinin (HA)-tagged ubiquitin vinyl methyl sulfone (VMS).

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UCHL5 affects proteolysis

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UCHL5 inhibits proteolysis.

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UCHL5 inhibits proteolysis. 6 / 6

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Importantly, whereas knockdown of POH1 interferes with the proteasome assembly, depletion of either USP14 or UCH37 alone does not affect or even slightly enhances protein degradation rates.

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The RNAi of UCHL5 or USP14 alone does not affect cell growth and proteasome composition but accelerates cellular protein degradation; however, RNAi of both UCHL5 and USP14 can inhibit cellular protein degradation.

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In contrast, RNAi of either UCHL5 or USP14 alone did not affect cell growth, proteasome structure, or proteolytic capacity, but increased the rate of protein degradation.

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In contrast, RNAi of Uch37 or Usp14 had no detectable effect on cell growth, proteasome structure or proteolytic capacity, but accelerated cellular protein degradation.

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RNAi of either Uch37 or USP14 (the mammalian homologue of yeast Ubp6) accelerates protein degradation.

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It has been shown that UCHL5 controls proteasome function and inhibition of UCHL5 promotes protein degradation in autophagy XREF_BIBR.

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UCHL5 activates proteolysis.

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It has been shown that UCHL5 controls proteasome function and inhibition of UCHL5 promotes protein degradation in autophagy XREF_BIBR.

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RNAi of both Uch37 and Usp14 also had no effect on proteasome structure or proteolytic capacity, but inhibited cellular protein degradation.

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26097878

UCHL5 affects Wnt

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UCHL5 activates Wnt.

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UCHL5 activates Wnt. 5 / 5

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Next, either wild type Uch37 (WT) or catalytically inactive Uch37 (IN) XREF_BIBR was reintroduced to determine if Uch37 could rescue Wnt signalling.

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Taken together, our results clearly demonstrate that Uch37 positively regulates Wnt signalling downstream of beta-catenin stabilization.

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UCH37 activates Wnt signaling and affects the expression of its target genes , such as beta-catenin , cyclin D1 and c-Myc , thereby increasing the cell growth of EC ( Liu et al. 2020 ) .

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Moreover, Wnt reporter activity in Xenopus embryos was completely rescued by Uch37 WT, but not by Uch37 IN mRNA (XREF_FIG).

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UCH37 activates Wnt signaling and affects the expression of its target genes , such as beta-catenin , cyclin D1 and c-Myc , thereby increasing the cell growth of EC .

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UCHL5 inhibits Wnt.

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UCHL5 inhibits Wnt. 1 / 1

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We also observed that downregulation of Uch37 inhibited ectopic Wnt activity that was induced by constitutively active LRP6 (LRP6DeltaN) and the GSK3beta inhibitor LiCl (XREF_SUPPLEMENTARY, g).

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UCHL5 increases the amount of Wnt.

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We hypothesized that deubiquitinating activity of Uch37 is involved in the ability of Tcf7 to activate transcription of Wnt target genes.

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UCHL5 decreases the amount of Wnt.

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Notably, we found that Uch37 MO antagonized expression of the Wnt target gene siamois but did not affect expression of target genes regulated by other signals (XREF_SUPPLEMENTARY), suggesting that endogenous Uch37 is specifically required for Wnt8 signalling.

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UCHL5 affects SMAD3

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UCHL5 activates SMAD3.

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UCHL5 increases the amount of SMAD3.

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Inhibition or down-regulation of UCHL5 reduced Smad2 and Smad3 levels and TGFbeta-1-induced the expression of FN and alpha-SMA in human lung fibroblast.

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UCHL5 decreases the amount of SMAD3.

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UCHL5 shRNA (# 2, # 3, not # 1, # 4) diminished protein levels of Smad2 and Smad3 (XREF_FIG).

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UCHL5 affects NFRKB

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UCHL5 activates NFRKB.

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UCHL5 activates NFRKB. 2 / 2

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UCHL5 aids resection by protecting NFRKB from proteasomal degradation.

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Further studies showed that DRAIC can promote the ubiquitination degradation of NFRKB mediated by UCHL5, and confirmed the inhibitory effect of DRAIC on proliferation and metastasis of GC cells, which could be rescued by oeNFRKB.

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UCHL5 bound to NFRKB activates NFRKB. 1 / 1

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DRAIC combined with UCHL5 and attenuated binding of UCHL5 and NFRKB, meanwhile promoting the degradation of NFRKB via ubiquitination, and then inhibited the proliferation and metastasis of GC cells, which can be rescued by oeNFRKB.

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UCHL5 decreases the amount of NFRKB.

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UCHL5 depletion did not, however, reduce NFRKB mRNA levels, nor protein levels of other INO80-complex subunits with suggested roles in DSB repair (XREF_SUPPLEMENTARY) XREF_BIBR - XREF_BIBR.

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We found that UCHL5 depletion reduced the steady-state level of NFRKB but not hRPN13 (XREF_FIG and data not shown); and time-course studies in cells treated with cycloheximide, to prevent de novo protein synthesis, revealed that UCHL5 depletion reduced NFRKB protein half-life (XREF_FIG).

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UCHL5 inhibits NFRKB.

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UCHL5 inhibits NFRKB. 1 / 1

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Furthermore, NFRKB reduction caused by UCHL5 depletion was rescued in cells expressing GFP-UCHL5 and was prevented by MG132 treatment (XREF_FIG and XREF_SUPPLEMENTARY).

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UCHL5 bound to NFRKB inhibits NFRKB. 1 / 1

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Benzyl isothiocyanate affects UCHL5

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Benzyl isothiocyanate inhibits UCHL5. 6 / 6

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BITC and PEITC inhibit USP9x and UCH37.

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Here we report that both BITC and PEITC inhibit USP9X and UCH37 and other DUBs at physiologically relevant concentrations and time scales.

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BITC and PEITC inhibit USP9x and UCH37 in vitro.

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Docking results suggest that benzyl isothiocyanate, phenethyl isothiocyanate, and DL-sulforaphane are more potent inhibitors of UCHL5 than USP14, and these ITCs could interact with the catalytic triads of UCHL5 and USP14.

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Both PEITC and BITC inhibited UCH37 with values of EC 50 of 36 +/- 5 muM and 31 +/- 6 muM, in reasonable agreement with the lysate assays (XREF_FIG and XREF_SUPPLEMENTARY).

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We observed a dose-dependent inhibition of UCHL5 by BITC ( xref , lower panel , lanes 3–5 vs .

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Aur affects UCHL5

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Aur inhibits UCHL5. 6 / 6

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We found that the remaining active forms of both UCHL5 and USP14 (i.e., those can be covalently bound by HA-UbVS) were clearly reduced in the 26S proteasomes pre-treated with Aur at 2 muM and became completely undetectable in those pre-treated with 40 muM Aur, indicating that Aur inhibits both UCHL5 and USP14.

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Here we report that (i) Aur shows proteasome-inhibitory effect that is comparable to that of bortezomib and Velcade (Vel); (ii) different from bortezomib, Aur inhibits proteasome associated deubiquitinases (DUBs) UCHL5 and USP14 rather than the 20S proteasome; (iii) inhibition of the proteasome associated DUBs is required for Aur induced cytotoxicity; and (iv) Aur selectively inhibits tumor growth in vivo and induces cytotoxicity in cancer cells from acute myeloid leukemia patients.

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However, we have recently unraveled that Aur inhibits 19S proteasome associated DUBs (mainly UCHL5 and USP14), accumulates ubiquitinated proteins (Ub-prs), and induces unfolded protein response (UPR) followed by cell apoptosis.

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Here we report that (i) Aur shows proteasome-inhibitory effect that is comparable to that of bortezomib/Velcade (Vel); (ii) different from bortezomib, Aur inhibits proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14 rather than the 20S proteasome; (iii) inhibition of the proteasome-associated DUBs is required for Aur-induced cytotoxicity; and (iv) Aur selectively inhibits tumor growth in vivo and induces cytotoxicity in cancer cells from acute myeloid leukemia patients.

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Molecularly, Aur inhibits 19S-associated DUBs USP14 and UCHL5 [ xref , xref ].

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We found that the remaining active forms of both UCHL5 and USP14 (i.e., those can be covalently bound by HA-UbVS) were clearly reduced in the 26S proteasomes pre-treated with Aur at 2 μM and became completely undetectable in those pre-treated with 40 μM Aur (Fig. xref ), indicating that Aur inhibits both UCHL5 and USP14.

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UCHL5 affects SNRPF

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UCHL5 decreases the amount of SNRPF. 4 / 4

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We also found that knockdown of UCH-L5 could upregulate the mRNA and protein level of SNRPF, while overexpression of UCH-L5 downregulated the mRNA and protein level of SNRPF in U87MG cells infected by Lentivirus.

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Accordingly, we found UCH-L5 inhibited mRNA expression and protein level of SNRPF both in U87MG cells and U251 cells significantly.

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Thus, the possible mechanism of UCH-L5 downregulates SNRPF expression may through interacting with NFRKB or other components of INO80 complex.

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To further confirm that UCH-L5 inhibits SNRPF expression, U87MG and U251 cells were subjected to analysis for lentivirus mediated gene knockdown and overexpression.

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Modified UCHL5 decreases the amount of SNRPF. 2 / 2

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Considering the function of UCH-L5 regulates DNA transcription and mRNA expression of the spliceosome components, the possible reason is that knockdown of UCH-L5 expression upregulates mRNA level of SNRPF which promots the splicing of downstream oncogenes, causing a promotion of oncogenic genes and tumorigenesis.

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UCHL5 affects homologous recombination

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UCHL5 activates homologous recombination. 5 / 5

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Specifically, UCHL5 promotes DNA-end resection and HR through regulating the stability of the NFRKB protein that is a subunit of chromatin remodeling complex INO80 [XREF_BIBR, XREF_BIBR].

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In addition to identifying many DUBs with DDR roles, this work also lead to establish that one, UCHL5 promotes DSB end resection and HR through regulating the stability of the NFRKB protein that is a subunit of chromatin remodeling complex INO80.

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UCHL5 (Ubiquitin carboxyl-terminal hydrolase isozyme L5) positively regulates DSB end resection and HR repair by deubiquitinating and stabilizing NFRKB protein (nuclear factor related to kappaB bindin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UCHL5 promotes HR and extensive DNA-end resection.

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Since INO80 chromatin remodeling complex had been implicated in DSB-end resection and DSB repair [97,98], UCHL5 may contribute HR via chromatin re-organization such as histone eviction.

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INO80 affects UCHL5

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INO80 activates UCHL5.

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INO80 activates UCHL5. 4 / 4

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In the nucleus, UCHL5 is also associated with human Ino80 chromatin remodeling complex and kept in inactive state, and then activated by transient interaction of the Ino80 complex with proteasome, suggesting that it may cooperate to regulate transcription or DNA repair XREF_BIBR.

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A possibility is that INO80 controls UCH-L5 in a temporal manner, where in some circumstances UCH-L5 is inhibited while under other circumstances post-translational modifications (PTMs) and/or conformational changes release the inhibition and activate UCH-L5, allowing for additional layers of regulation.

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Intriguingly, Uch37 is held in an inactive state in the INO80 complex but, at least in vitro, can be activated by transient interaction of the INO80 complex with proteasomes [26].

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Curiously, INO80 associated UCH37 can be activated by transient incubation with either RPN13 or 26S proteasome lacking UCH37, without UCH37 dissociating from the INO80 complex.

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INO80 inhibits UCHL5.

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INO80 inhibits UCHL5. 1 / 1

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The essential cysteine protease UCH-L5 is activated by proteasome ubiquitin receptor RPN13 (ADRM1) or inhibited by chromatin remodeling complex component INO80 (NFRKB) [XREF_BIBR].

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UCHL5 affects IL1B

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UCHL5 inhibits IL1B.

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UCHL5 inhibits IL1B. 2 / 2

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It is possible that the level of UCH37 silencing we achieved with siRNA may not have been sufficient to observe a measurable effect on nigericin induced IL-1beta release.

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However, inhibition of USP14 activity with IU1, silencing of UCH37 with siRNA, or a combination of both approaches to inhibit both USP14 and UCH37 simultaneously did not inhibit the release of IL-1beta (XREF_FIG).

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UCHL5 activates IL1B.

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UCHL5 activates IL1B. 2 / 2

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We also showed that overexpression of UCH-L5 was associated with a significant increase in caspase-1 activity, while inhibition of UCH-L5 by selective inhibitor [XREF_BIBR] or UCH-L5 knock-down led to decrease in inflammasome dependent IL-1beta release in chicken as well as in human macrophages during infection with Salmonella and during inflammasome activation by lipopolysaccharide (LPS) and nigericin.

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UCH-L5 inhibition down-regulates IL-1beta release during inflammasome activation in macrophages.

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UCHL5 increases the amount of IL1B.

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UCHL5 increases the amount of IL1B. 1 / 1

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Whether USP7 and USP47 directly interact with NLRP3 receptor or with other inflammasome component was not investigated.Enzymatic activity of UCHL5 (from the ubiquitin C-terminal hydrolase family) is also increased after Salmonella enterica serovar Typhimurium infection, and UCHL5 silencing leads to impaired release of IL-1b after infection [57] .

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Valproic acid affects UCHL5

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Phenethyl isothiocyanate affects UCHL5

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Phenethyl isothiocyanate inhibits UCHL5. 4 / 4

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Both PEITC and BITC inhibited UCH37 with values of EC 50 of 36 +/- 5 muM and 31 +/- 6 muM, in reasonable agreement with the lysate assays (XREF_FIG and XREF_SUPPLEMENTARY).

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Here we report that both BITC and PEITC inhibit USP9X and UCH37 and other DUBs at physiologically relevant concentrations and time scales.

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BITC and PEITC inhibit USP9x and UCH37 in vitro.

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BITC and PEITC inhibit USP9x and UCH37.

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Auranofin affects UCHL5

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Auranofin inhibits UCHL5. 4 / 4

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Auranofin (Aur) inhibits proteasome associated deubiquitinases (DUBs) UCHL5 and USP14 rather than the 20S proteasome; inhibition of the proteasome associated DUBs is required for Aur induced cytotoxicity; and Aur selectively inhibits tumor growth in vivo and induces cytotoxicity in cancer cells from patients with acute myeloid leukemia [XREF_BIBR].

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The computational model also indicates that an active metabolite of auranofin can inhibit UCHL5 and USP14.

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Auranofin was recently reported to inhibit proteasome activity at the level of the proteasome associated deubiquitinases (DUBs) UCHL5 and USP14.

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HA-UbVS pretreatment of auranofin could bind the HA tagged UbVS in the purified 26S proteasome, supporting that auranofin inhibits UCHL5 and USP14.

26097878

UCHL5 affects TCF7

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UCHL5 inhibits TCF7.

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UCHL5 inhibits TCF7. 2 / 2

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The increased expression of UCH37 decreases the polyubiquitin of TCF7.

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To test this hypothesis, we first depleted endogenous Uch37 to suppress Tcf7 mediated activation of target genes (XREF_FIG) and Tcf7 mediated reporter activity (XREF_FIG).

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UCHL5 activates TCF7.

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UCHL5 activates TCF7. 2 / 2

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Importantly, we observed that knockdown of Uch37 by Uch37 MO inhibited binding of Tcf7 to target gene promoters (XREF_FIG lane 3).

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Fractionation and immunostaining analyses in Xenopus gastrula showed that Uch37 co-localized with Tcf7 in the nucleus where Tcf7 protein exclusively resides despite both cytoplasmic and nuclear localization of Uch37 protein (XREF_SUPPLEMENTARY), raising the possibility that the nuclear pool of Uch37 regulates Tcf7 to activate Wnt signalling.

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PTPN2 affects UCHL5

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PTPN2 inhibits UCHL5.

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PtPT significantly inhibited USP14 and UCHL5, thereby accumulating Ub-conjugates.

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PtPT significantly inhibited USP14 and UCHL5, thereby accumulating Ub-conjugates.

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PTPN2 activates UCHL5.

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PTPN2 activates UCHL5. 2 / 2

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PtPT inhibits the UPS by targeting DUBs USP14 and UCHL5 associated with 26S proteasomes.

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These computational and experimental results indicate that PtPT can selectively target UCHL5 and USP14, two proteasome associated DUBs.

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Methylmercury chloride affects UCHL5

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Methylmercury chloride increases the amount of UCHL5. 3 / 3

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PSMD4 affects UCHL5

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PSMD4 inhibits UCHL5. 3 / 3

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Interestingly, we found that different from bortezomib, AF inhibits 19S proteasome associated DUBs UCHL5 and USP14 but not the 20S proteasome activity.

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Interestingly, we found that different from bortezomib, AF inhibits 19S proteasome-associated DUBs UCHL5 and USP14 but not the 20S proteasome activity.

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This was also confirmed by computational molecular docking, K48 linked polyubiquitin disassembly, and HA-UbVS competitive binding assay; these experiments showed that AF might inhibit the proteasomal cysteine DUBs UCHL5 and USP14.

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Pyrithione affects UCHL5

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Pyrithione activates UCHL5.

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Pyrithione activates UCHL5. 2 / 2

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Another compound, copper pyrithione (CuPT), was reported to target both 19S proteasome specific DUBs, UCH37 and USP14, as well as 20S proteolytic peptidases.

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Here we report that zinc pyrithione (ZnPT) targets the proteasome associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes.

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Pyrithione inhibits UCHL5.

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Pyrithione inhibits UCHL5. 1 / 1

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And only recently we have definitely confirmed that nickel pyrithione (NiPT) inhibits the 19S proteasome-associated deubiquitinases (DUBs) USP14 and UCHL5, but not the 20S proteasome peptidases, and the inhibition of proteasome-associated DUBs induces NiPT-mediated cytotoxicity, revealing a novel mechanism for the anti-cancer effects of nickel-containing compounds [ xref ].

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UCHL5 affects Ser-Met

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UCHL5 inhibits Ser-Met.

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UCHL5 inhibits Ser-Met. 2 / 2

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And we found UCH-L5 downregulated mRNA level of other Sm genes.

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In stable UCH-L5 knockdown and stable UCH-L5 overexpressing U87MG cells, we found that knockdown UCH-L5 expression upregulated mRNA level of Sm genes except for SNRPN (XREF_SUPPLEMENTARY), while UCH-L5 overexpression downregulates mRNA level of Sm genes in U87MG cells (XREF_SUPPLEMENTARY).

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UCHL5 decreases the amount of Ser-Met.

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UCHL5 decreases the amount of Ser-Met. 1 / 1

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Thus, we thought UCH-L5 may inhibit transcription of Sm genes.

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HAUS7 affects UCHL5

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HAUS7 inhibits UCHL5. 1 / 2

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UIP1 may modulate the ubiquitinated protein turnover by blocking the association of UCH37 with the 26S proteasome.

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HAUS7 bound to UCHL5 inhibits UCHL5. 1 / 1

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We postulate that UIP1 binds the C-terminal extension of UCH37 preferentially and thus blocks the association of UCH37 with PA700 in the 26S proteasome.The biological functions of UCH37 are still uncl[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UCHL5 affects CTNNB1

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UCHL5 increases the amount of CTNNB1.

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UCHL5 increases the amount of CTNNB1. 1 / 1

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Meanwhile, deletion of UCH37 decreased the levels of beta-catenin and the early endosomal protein Rab8.

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UCHL5 decreases the amount of CTNNB1.

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UCHL5 decreases the amount of ubiquitinated CTNNB1. 1 / 1

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We further found that deletion of UCH37 increased the levels of the ubiquitinated beta-catenin and accelerated the hydrogen peroxide stimulated degradation of beta-catenin.

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UCHL5 activates CTNNB1.

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UCHL5 activates CTNNB1. 1 / 1

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Proteasomal deubiquitinase UCH37 inhibits degradation of beta-catenin and promotes cell proliferation and motility.

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Sulforaphane affects UCHL5

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When lysates of MDA-MB-231 cells treated with 25 µM of SFN were used in the Ub-VS assay, inhibition of both USP14 and UCHL5 by SFN was observed ( xref , lanes 3 vs .

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Paraquat affects UCHL5

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Paraquat increases the amount of UCHL5. 2 / 2

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Ethanol affects UCHL5

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Ethanol decreases the amount of UCHL5. 2 / 2

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Consistent with previous findings, we discovered that ethanol feeding decreased the levels of Ecm29 and UCHL5.

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Dibutyl phthalate affects UCHL5

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Dibutyl phthalate decreases the amount of UCHL5. 2 / 2

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Cyclosporin A affects UCHL5

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Cyclosporin A increases the amount of UCHL5. 2 / 2

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Bortezomib affects UCHL5

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Bortezomib inhibits UCHL5. 2 / 2

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Notwithstanding this success, the potency of pimozide (IC50 ~2 μM) is lower than those of clinically approved UPS inhibitor 26S proteasome inhibitor Bortezomib (IC50 ~100 nM) (Fig. 1 and Table 2), and another UPS inhibitor VLX1570, which inhibited the DUBs UCHL5 and USP14 (IC50 ~100 nM) and was previously studied in clinical trials but terminated due to limiting toxicities (study identifier NCT02372240) (ClinicalTrials.gov, 2018; Wang et al., 2016).

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Notwithstanding this success, the potency of pimozide (IC 50 ~ 2muM) is lower than those of clinically approved UPS inhibitor 26S proteasome inhibitor Bortezomib (IC 50 ~ 100nM) (XREF_FIG and XREF_TABLE), and another UPS inhibitor VLX1570, which inhibited the DUBs UCHL5 and USP14 (IC 50 ~ 100nM) and was previously studied in clinical trials but terminated due to limiting toxicities (study identifier NCT02372240).

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Bisphenol A affects UCHL5

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Bisphenol A increases the amount of UCHL5. 2 / 2

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Benzo[a]pyrene affects UCHL5

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Benzo[a]pyrene increases the amount of UCHL5. 2 / 2

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Ubiquitin affects UCHL5

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Ubiquitin activates UCHL5. 2 / 2

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Recently it was reported that UCH37 activity is stimulated by branched ubiquitin chain architectures.

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It associates with the 19S RP via the Rpn13 subunit, the proteasomal ubiquitin receptor that activates Uch37 deubiquitylating activity.

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USP14 affects UCHL5

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USP14 inhibits UCHL5. 2 / 2

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By using overexpression model of chicken UCH-L5 and b-AP15 inhibitor of UCH-L5 and USP14 [XREF_BIBR], which inhibited UCH-L5 at low molar concentration, but it did not significantly inhibit other DUBs in HD11 cells (XREF_SUPPLEMENTARY), we observed the overexpression of UCH-L5 had a negative effect on cell viability, which depended on its catalytic activity as a DUB, since if UCH-L5 overexpressing cells were treated with b-AP15 inhibitor, the cell viability was partially restored (XREF_FIG).

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We also found that inhibition of USP-14 and UCHL5 activities by the ITCs caused increased levels of USP14 and UCHL5 proteins, but not the third 19S deubiquitinating enzyme (DUB), POH1 and RPN11, suggesting feedback loop activation and further supporting that ITCs are inhibitors of proteasomal cysteine DUBs.

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UCHL5 affects wnt8

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UCHL5 activates wnt8. 2 / 2

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Ectopic expression of Uch37 mRNA enhanced the ability of Wnt8 to form a secondary axis, whereas depletion of Uch37 by Uch37 MO efficiently inhibited it (XREF_FIG, XREF_SUPPLEMENTARY).

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Importantly, reintroduction of Uch37 WT mRNA restored the ability of Wnt8 to induce Xpo, Vent1 and Vent2 expression, whereas Uch37 IN mRNA did not (XREF_FIG lane 7 and 8).

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UCHL5 affects localization

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UCHL5 activates localization. 2 / 2

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The human homologue UCH37 was reported to promote Smo localization to cilia.

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Uchl5 stabilizes Drosophila Smo and promotes its localization on the cell surface.

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UCHL5 affects DNA Breaks, Double-Stranded

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UCHL5 activates DNA Breaks, Double-Stranded. 2 / 2

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UCHL5 affects Cell Survival

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UCHL5 inhibits Cell Survival. 2 / 2

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USP14 and UCHL5 short interfering RNA knockdown decreases MM cell viability.

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Knock-down of UCHL5 expression in non small cell lung carcinoma cells resulted in alterations in components of the mitochondrial apoptosis pathway including down-regulation of the anti-apoptotic Bcl-2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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SLFN12 affects UCHL5

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Modified SLFN12 increases the amount of UCHL5. 2 / 2

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SLFN12 or SERPB12 overexpression increases expression of the complementary deubiquitylases USP14 and UCHL5 in vitro, and SERPB12 stimulates USP14 deubiquitylase activity.

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Either SLFN12 overexpression (XREF_FIG and XREF_FIG) or SERPB12 overexpression (XREF_FIG and XREF_FIG) increased both USP14 (XREF_FIG and XREF_FIG) and UCHL5 (XREF_FIG and XREF_FIG) expression.

30045019

N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal affects UCHL5

| 1

N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal inhibits UCHL5. 1 / 2

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As HA-UCHL5 was expressed under a constitutive CMV promoter in a plasmid containing only the coding sequence, MG132 dependent reduction of UCHL5 was most likely a post-transcriptional regulatory effec[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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E2F1 affects UCHL5

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E2F1 increases the amount of UCHL5. 1 / 2

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Interestingly, UCH37 expression is induced by E2F1, and its level rises in G1/S transition and S phase, suggesting a positive feedback loop between UCH37 and E2F1.

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Proteasome inhibitor affects UCHL5

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Proteasome inhibitor inhibits UCHL5.

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Proteasome inhibitor inhibits UCHL5. 1 / 1

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Notwithstanding this success, the potency of pimozide (IC 50~2 μM) is lower than those of clinically approved UPS inhibitor 26S proteasome inhibitor Bortezomib (IC 50~1 00 nM) ( Fig. 1 and Table 2 ), and another UPS inhibitor VLX1570, which inhibited the DUBs UCHL5 and USP14 (IC 50~1 00 nM) and was previously studied in clinical trials but terminated due to limiting toxicities (study identifier NCT02372240) (ClinicalTrials.gov, 2018; Wang et al., 2016) .

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Proteasome inhibitor activates UCHL5.

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Proteasome inhibitor activates UCHL5. 1 / 1

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UCHL5 affects cell death

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UCHL5 inhibits cell death.

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UCHL5 inhibits cell death. 1 / 1

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We therefore speculate that a decrease in expression of Uch-L5 mediates testicular I-R-induced apoptotic cell death and defects in spermatogenesis Zinc finger AN1-type domain 3 (ZFAND3), also known as testis expressed sequence 27 (Tex27), was originally detected in mouse testis [XREF_BIBR].

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UCHL5 activates cell death.

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UCHL5 activates cell death. 1 / 1

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Overexpression of UCH-L5 (but not overexpression of UCH-L3) for two days prior to the infection with Salmonella for one hour also lead to significant cell death (XREF_FIG), while cell treatment with b-AP15 inhibitor prior to Salmonella infection led to slight increase in cell viability in comparison to vehicle treated cells (XREF_SUPPLEMENTARY).

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UCHL5 affects TP53

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UCHL5 inhibits TP53.

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UCHL5 inhibits TP53. 1 / 1

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Similarly, knockdown of UCH37 and USP14 or b-AP15 treatment rescued p53 protein, induced by COPS5 overexpression, and enhanced the activity of transfected luciferase reporter plasmids for p53, Bax, and p21 expression and protein levels of p53 downstream target genes BAX and p21.

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UCHL5 increases the amount of TP53.

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Modified UCHL5 increases the amount of TP53. 1 / 1

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We found that p53 protein level was rescued after knockdown of COPS5 and induced by UCH37 and USP14 overexpression.

32257396

UCHL5 affects SMO

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UCHL5 increases the amount of SMO.

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UCHL5 increases the amount of SMO. 1 / 1

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Furthermore, knockdown of UCH37 in NIH3T3 cells reduced human Smo level and Shh pathway activity, suggesting that UCHL5/UCH37 plays a conserved role in modulating Smo ubiquitination and turnover [44].

| PMC

UCHL5 activates SMO.

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UCHL5 activates SMO. 1 / 1

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The human homologue UCH37 was reported to promote Smo localization to cilia.

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UCHL5 affects FN1

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UCHL5 increases the amount of FN1.

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UCHL5 increases the amount of FN1. 1 / 1

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As shown in XREF_FIG, UCHL5 knockdown attenuated expression of FN and alpha-SMA induced by TGFbeta-1, which is consistent with b-AP15 treatment in XREF_FIG.

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UCHL5 decreases the amount of FN1.

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UCHL5 decreases the amount of FN1. 1 / 1

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Additionally, high glucose induced p21 (WAF1), fibronectin protein expression and cell hypertrophy were attenuated by UCHL5 shRNA.

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UCHL5 affects Caspase

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UCHL5 increases the amount of Caspase.

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Modified UCHL5 increases the amount of Caspase. 1 / 1

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The authors went on to demonstrate that UCHL5 expression increases IL‐1β secretion, and increases the levels of caspase‐1, a key member of the inflammasome that processes pro‐IL‐1β into its active form.

28196299

UCHL5 activates Caspase.

| 1

UCHL5 activates Caspase. 1 / 1

| 1

➶

reach

22819849

UCHL5 affects COPS5

| 2

UCHL5 increases the amount of COPS5.

| 1

UCHL5 increases the amount of COPS5. 1 / 1

| 1

➶

reach

We further found that UCH37 significantly upregulated the protein level of COPS5, but there is no obvious change for other candidate interacting protein, including RPN10, HAUS7, and RPN13.

32257396

UCHL5 decreases the amount of COPS5.

| 1

Modified UCHL5 decreases the amount of COPS5. 1 / 1

| 1

➶

reach

UCH37 overexpression decreased the ubiquitination level of COPS5; in contrast, ubiquitination COPS5 significantly increased after treatment with b-AP15 in vitro and the protein level of COPS5 decreased in vivo in heterozygous p53 +/- mice.

32257396

UCHL5 affects CASP1

| 2

UCHL5 increases the amount of CASP1.

| 1

Modified UCHL5 increases the amount of CASP1. 1 / 1

| 1

➶

reach

The authors went on to demonstrate that UCHL5 expression increases IL-1b secretion, and increases the levels of caspase-1, a key member of the inflammasome that processes pro-IL-1b into its active form.

28196299

UCHL5 activates CASP1.

| 1

UCHL5 activates CASP1. 1 / 1

| 1

➶

reach

The data indicate that overexpression of UCH-L5 leads to significantly increased caspase-1 activity.

26267804

TGFB affects UCHL5

| 1 1

TGFB increases the amount of UCHL5.

| 1

TGFB increases the amount of UCHL5. 1 / 1

| 1

➶

reach

UCH37 especially influences TGFbeta mediated transcription during the early phase of TGFbeta receptor activation.

25007997

TGFB activates UCHL5.

| 1

TGFB activates UCHL5. 1 / 1

| 1

➶

eidos

In contrast , C-CBL , heat shock protein 90 ( Hsp90 ) , transforming growth factor-beta stimulated clone 22 ( TSC-22 ) , tumor necrosis factor receptor-associated factor 4 ( TRAF4 ) , ubiquitin-specific protease 4 ( USP4 ) , ubiquitin-specific protease 11 ( USP11 ) , ubiquitin-specific protease 15 ( USP15 ) , and UCH37 can stabilize the receptor by blocking the ubiquitination of the receptor [ 103-110 ] , thereby activating the TGF-beta signaling pathway .

| PMC

LEP affects UCHL5

| 1 1

LEP inhibits UCHL5.

| 1

LEP inhibits UCHL5. 1 / 1

| 1

➶

sparser

In addition, the OBs used in this research have shown their antiproliferative activity associated with their DUB-suppressing activities in a dose-dependent manner, suggesting that inhibition of UCHL5 and USP14 by OBs are functional, that would generate toxicity in normal tissues.

30963630

LEP decreases the amount of UCHL5.

| 1

LEP decreases the amount of UCHL5. 1 / 1

| 1

➶

reach

As reported earlier, Ob rats showed increased UCHL1 expression and decreased UCHL5 expression when compared to lean rats and expression pattern of these two DUBs in PF rats was similar to that of lean[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

27260470

Urethane affects UCHL5

1 |

Urethane decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

28818685

Trimellitic anhydride affects UCHL5

1 |

Trimellitic anhydride increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

19042947

Triclosan affects UCHL5

1 |

Triclosan decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

29596926

Trichostatin A affects UCHL5

1 |

Trichostatin A increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

24935251

Topotecan affects UCHL5

1 |

Topotecan decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

25729387

Streptozocin affects UCHL5

1 |

Streptozocin increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

30980806

Sodium(1+) affects UCHL5

| 1

Sodium(1+) activates UCHL5. 1 / 1

| 1

➶

reach

Additional deleted genes in the region include multiple members of the Regulator of G protein Signaling Gene family (RGS1, RGS2, RGS13, and RGS18) as well as TROVE Domain Family Member 2, Ubiquitin C-terminal Hydrolase L5, and portions of Potassium Sodium Activated Channel Subfamily Member 2 (TROVE2, UCHL5, and KCNT2).

29264543

Sodium arsenite affects UCHL5

1 |

Sodium arsenite increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

29361514

Silicon dioxide affects UCHL5

1 |

Silicon dioxide increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

25895662

Serum insulin affects UCHL5

1 |

Serum insulin decreases the amount of UCHL5. 1 / 1

1 |

➶

bel

Below are the contents of a table from the paper

12031981

Proteasome subunit affects UCHL5

| 1

Proteasome subunit activates UCHL5. 1 / 1

| 1

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reach

We also find that proteasome subunit RPN13, an activator of UCHL5, could enhance the effect of UCHL5 on Smo protein level.

28992318

Potassium(1+) affects UCHL5

| 1

Potassium(1+) activates UCHL5. 1 / 1

| 1

➶

reach

29264543

Piroxicam affects UCHL5

1 |

Piroxicam decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

21858171

Piperidin-2-one affects UCHL5

| 1

Piperidin-2-one inhibits UCHL5. 1 / 1

| 1

➶

reach

We here explored the phenotypic response of colon cancer cells to b-AP15, a bis-benzylidine piperidone previously shown to inhibit the proteasome deubiquitinases (DUBs) USP14 and UCHL5.

30149015

Phorbol 13-acetate 12-myristate affects UCHL5

1 |

Phorbol 13-acetate 12-myristate increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

25613284

Phlorizin affects UCHL5

1 |

Phlorizin decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

22538082

Paclitaxel affects UCHL5

1 |

Paclitaxel increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

18754875

Oxaliplatin affects UCHL5

1 |

Oxaliplatin decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

25729387

Nimesulide affects UCHL5

1 |

Nimesulide increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

24136188

Nickel(2+) affects UCHL5

| 1

Nickel(2+) activates UCHL5. 1 / 1

| 1

➶

reach

This novel nickel complex can also target proteasomal DUBs (UCHL5 and USP14) and induce apoptosis in cancer cells [XREF_BIBR].

29039082

Nefazodone affects UCHL5

1 |

Nefazodone increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

24136188

Molybdenum atom affects UCHL5

| 1

Molybdenum atom activates UCHL5. 1 / 1

| 1

➶

reach

Because both Tcf7 and Lef1 have functional redundancy for ventrolateral mesoderm development as a Wnt activator XREF_BIBR, the rescue of MO effect by co-injection of Lef1 mRNA supports a specific role of Uch37 in Tcf7 regulation for ventrolateral mesoderm development.

28198400

Molecule affects UCHL5

| 1

Molecule inhibits UCHL5. 1 / 1

| 1

➶

eidos

This small molecule selectively blocks UCH-L5 and USP14 [ 77 ] .

| PMC

Methylmercury compound affects UCHL5

1 |

Methylmercury compound increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

26558463

Methyl methanesulfonate affects UCHL5

1 |

Methyl methanesulfonate decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

23649840

Metabolite affects UCHL5

| 1

Metabolite inhibits UCHL5. 1 / 1

| 1

➶

sparser

The computational model also indicates that an active metabolite of auranofin can inhibit UCHL5 and USP14.

26097878

Maneb affects UCHL5

1 |

Maneb increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

18386188

Maleimide affects UCHL5

| 1

Maleimide activates UCHL5. 1 / 1

| 1

➶

reach

Briefly, UCH37 samples (+/-PEITC) were treated with isotopically heavy N-ethyl maleimide (d5-NEM) to cap all exposed and reactive cysteine residues.

28881649

Isothiocyanate affects UCHL5

| 1

Isothiocyanate inhibits UCHL5. 1 / 1

| 1

➶

sparser

We previously reported that phenethyl isothiocyanate (PEITC) inhibits two deubiquitinases (DUBs), USP9x and UCH37.

28881649

Irinotecan affects UCHL5

1 |

Irinotecan decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

15956246

Ionomycin affects UCHL5

1 |

Ionomycin increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

25613284

Hydroperoxide affects UCHL5

1 |

Hydroperoxide increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

18951874

Hsa-miR-9500 affects UCHL5

1 |

Hsa-miR-9500 decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-6883-3p affects UCHL5

1 |

Hsa-miR-6883-3p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-6872-3p affects UCHL5

1 |

Hsa-miR-6872-3p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-6822-5p affects UCHL5

1 |

Hsa-miR-6822-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-6750-5p affects UCHL5

1 |

Hsa-miR-6750-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-657 affects UCHL5

1 |

Hsa-miR-657 decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-6512-5p affects UCHL5

1 |

Hsa-miR-6512-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-5584-5p affects UCHL5

1 |

Hsa-miR-5584-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-5581-3p affects UCHL5

1 |

Hsa-miR-5581-3p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-539-3p affects UCHL5

1 |

Hsa-miR-539-3p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-5006-3p affects UCHL5

1 |

Hsa-miR-5006-3p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-485-3p affects UCHL5

1 |

Hsa-miR-485-3p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-4755-5p affects UCHL5

1 |

Hsa-miR-4755-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-454-5p affects UCHL5

1 |

Hsa-miR-454-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-4446-5p affects UCHL5

1 |

Hsa-miR-4446-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-3665 affects UCHL5

1 |

Hsa-miR-3665 decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-3185 affects UCHL5

1 |

Hsa-miR-3185 decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-2681-5p affects UCHL5

1 |

Hsa-miR-2681-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Hsa-miR-1322 affects UCHL5

1 |

Hsa-miR-1322 decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23592263

Hsa-miR-1-5p affects UCHL5

1 |

Hsa-miR-1-5p decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:mirtarbase

No evidence text available

23824327

Glucose affects UCHL5

| 1

Glucose increases the amount of UCHL5. 1 / 1

| 1

➶

reach

High glucose also increased UCHL5 protein expression, which was attenuated by LY294002, the dominant negative p85 and the dominant negative CREB.

23500140

Genistein affects UCHL5

1 |

Genistein increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

24552547

Formaldehyde affects UCHL5

1 |

Formaldehyde decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

23649840

Flutamide affects UCHL5

1 |

Flutamide increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

24136188

Finasteride affects UCHL5

1 |

Finasteride increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

24136188

Ethyl methanesulfonate affects UCHL5

1 |

Ethyl methanesulfonate decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

23649840

Dorsomorphin affects UCHL5

1 |

Dorsomorphin increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

27188386

Disodium selenite affects UCHL5

1 |

Disodium selenite increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

18175754

Dimethyl sulfoxide affects UCHL5

| 1

Dimethyl sulfoxide activates UCHL5. 1 / 1

| 1

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reach

Control cells treated with b-AP15 inhibitor of UCH-L5 had lower caspase-1 activity than control cells treated with vehicle control (DMSO; XREF_FIG).

26267804

Dicrotophos affects UCHL5

1 |

Dicrotophos decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

28302478

Diarsenic trioxide affects UCHL5

1 |

Diarsenic trioxide increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

20458559

Curcumin affects UCHL5

| 1

Curcumin inhibits UCHL5. 1 / 1

| 1

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reach

USP14 and UCH37 are also inhibited by curcumin analogue AC17.

28279784

Coumestrol affects UCHL5

1 |

Coumestrol increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

19167446

Copper(2+) affects UCHL5

| 1

Copper(2+) activates UCHL5. 1 / 1

| 1

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reach

Another compound, copper pyrithione (CuPT), was reported to target both 19S proteasome specific DUBs, UCH37 and USP14, as well as 20S proteolytic peptidases.

26295307

Carbon nanotube affects UCHL5

1 |

Carbon nanotube increases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

25554681

All-trans-retinoic acid affects UCHL5

1 |

All-trans-retinoic acid decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

21934132

Acetaldehyde affects UCHL5

| 1

Acetaldehyde inhibits UCHL5. 1 / 1

| 1

➶

reach

To determine whether DUBs of the 26S proteasome regulate proteasomal ubiquitination, we set up in vitro ubiquitination reactions in which Ub aldehyde (an inhibitor of both Usp14 and Uch37) or 1,10-phenanthroline (an inhibitor of Rpn11) was added in the reactions.

24743594

ZEB1 affects UCHL5

1 |

ZEB1 decreases the amount of UCHL5. 1 / 1

1 |

➶

biopax:msigdb

No evidence text available

UVI 3003 affects UCHL5

1 |

UVI 3003 decreases the amount of UCHL5. 1 / 1

1 |

➶

ctd

No evidence text available

25581642

ULD affects UCHL5

| 1

ULD activates UCHL5. 1 / 1

| 1

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reach

First, ULD conformational changes allow INO80G DEU helix alpha6 to contact the UCH-L5 CD, possibly stabilizing the inhibitory conformation of the ULD (XREF_FIG D and S1D).

25702870

UCHL5 affects translation

| 1

UCHL5 inhibits translation. 1 / 1

| 1

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reach

In order to understand the endogenous function of Uch37 in Xenopus, as suggested by its local enrichment in the mesodermal region of the embryo, we knocked down endogenous Uch37 by injecting antisense morpholino oligonucleotides (Uch37 MO) that specifically and efficiently blocked translation of Uch37 protein (XREF_SUPPLEMENTARY).

28198400

UCHL5 affects transcription, DNA-templated

| 1

UCHL5 activates transcription, DNA-templated. 1 / 1

| 1

➶

reach

Furthermore, overexpression of UCH37 upregulates TGF-beta-dependent transcription, and this effect is reversed in cells subject to RNAi mediated knockdown of endogenous UCH37.

16027725

UCHL5 affects sub

| 1

UCHL5 activates sub. 1 / 1

| 1

➶

reach

Despite its importance, however, little is known about how and when UCH-L5 rescues specific substrates by exerting DUB activity.

28338014

UCHL5 affects molybdenum atom

| 1

UCHL5 activates molybdenum atom. 1 / 1

| 1

➶

reach

However, equal concentrations of Uch37 IN mRNA did not rescue the MO effect (XREF_FIG lane 5).

28198400

UCHL5 affects cell cycle

| 1

UCHL5 activates cell cycle. 1 / 1

| 1

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reach

UCHL5 knockdown in LUAD cells significantly inhibited cell proliferation and reduced the expression of key cell cycle proteins.

33046988

UCHL5 affects bortezomib

| 1

UCHL5 activates bortezomib. 1 / 1

| 1

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reach

Small molecule inhibitors of UCHL5 could induce apoptosis of multiple myeloma cells and reverse bortezomib resistance [XREF_BIBR].

32351584

UCHL5 affects ZUP1

| 1

UCHL5 inhibits ZUP1. 1 / 1

| 1

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reach

This study indirectly demonstrated that USP14 and/or UCHL5 partakes in decreasing DR5 expression.MCPIP1 is another DUB that decreases DR5 [79].

31208841

UCHL5 affects Ubiquitinated Proteins

| 1

UCHL5 inhibits Ubiquitinated Proteins. 1 / 1

| 1

➶

eidos

Functional studies suggest that UCH-37 inhibits the degradation of ubiquitinated proteins by the proteasome by removing ubiquitin from the distal end of the polyubiquitin chain ( 59 ) .

19489724

UCHL5 affects USP14

| 1

UCHL5 inhibits USP14. 1 / 1

| 1

➶

reach

30015387

UCHL5 affects UCHL3

| 1

UCHL5 activates UCHL3. 1 / 1

| 1

➶

reach

26267804

UCHL5 affects TRIB2

| 1

UCHL5 inhibits TRIB2. 1 / 1

| 1

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reach

However, neither the DUB inhibitor VLX1570 or EOAI nor the depletion of key DUBs, USP14, and UCH37 30, abolished the effect of TRIB2 in Bel-7402 and SMMC-7721 cells, excluding the possibility that TRIB2 regulates Ub via these DUBs.

33414446

UCHL5 affects TGFBR1

1 |

UCHL5 increases the amount of TGFBR1. 1 / 1

1 |

➶

signor

Smad7 can act as an adaptor able to recruit uch37 to the type i tgf-beta receptor. Consequently, uch37 dramatically up-regulates tgf-beta-dependent gene expression by de-ubiquitinating and stabilizing the type i tgf-beta receptor.

17052192

UCHL5 affects SMAD7

1 |

UCHL5 activates SMAD7. 1 / 1

1 |

➶

signor

16027725

UCHL5 affects SLFN12

| 1

UCHL5 activates SLFN12. 1 / 1

| 1

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reach

This, in turn, represents a key mechanism by which these proteins influence enterocytic differentiation since the SLFN12 effects are blocked by pharmacologic inhibition or molecular reduction of the deubuiquitylases USP14 and UCHL5.

30045019

UCHL5 affects SI

| 1

UCHL5 activates SI. 1 / 1

| 1

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reach

We further confirmed that reduction of both UCHL5 and USP14 blocked the induction of SI by SLFN12 at the protein level (XREF_FIG).

30045019

UCHL5 affects SERPINE1

| 1

UCHL5 increases the amount of SERPINE1. 1 / 1

| 1

➶

reach

UCH37 knockdown significantly inhibits the activity of a TGF-beta-dependent gene reporter and selectively decreases levels of some TGF-beta-dependent target genes, notably p21, a protein which plays a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23220010

UCHL5 affects RPN13

| 1

UCHL5 inhibits RPN13. 1 / 1

| 1

➶

reach

Uch37 knockdown in the same cell line led to decreased deubiquitination activity XREF_BIBR, XREF_BIBR and expression of the C-terminal domain of Rpn13, that competes for the binding to Uch37, reduced proteolytic activity XREF_BIBR, XREF_BIBR.

21048919

UCHL5 affects RAB8A

| 1

UCHL5 increases the amount of RAB8A. 1 / 1

| 1

➶

reach

Meanwhile, deletion of UCH37 decreased the levels of beta-catenin and the early endosomal protein Rab8.

30726867

UCHL5 affects Polyubiquitin

| 1

UCHL5 inhibits Polyubiquitin 1 / 1

| 1

➶

reach

The increased expression of UCH37 decreases the polyubiquitin of TCF7.

32486158

UCHL5 affects Neoplasm Metastasis

| 1

UCHL5 inhibits Neoplasm Metastasis. 1 / 1

| 1

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reach

And the above findings suggest that UCH-L5 may inhibit occurrence and metastasis of gliomas.

29371935

UCHL5 affects NFKBIA

| 1

UCHL5 activates NFKBIA. 1 / 1

| 1

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reach

Knockdown of Uch37 was recently found to inhibit degradation of IkappaBalpha and inducible nitric oxide synthase in several cell lines [XREF_BIBR].

23290100

UCHL5 affects Multiple Myeloma

| 1

UCHL5 inhibits Multiple Myeloma. 1 / 1

| 1

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reach

USP14 and UCHL5 short interfering RNA knockdown decreases MM cell viability.

24319254

UCHL5 affects MYC

| 1

UCHL5 increases the amount of MYC. 1 / 1

| 1

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reach

Deletion of UCH37 also down-regulated the transcription of c-Myc, a downstream effector of beta-catenin, and inhibited cell proliferation and motility.

30726867

UCHL5 affects Ile-Leu

| 1

UCHL5 increases the amount of Ile-Leu. 1 / 1

| 1

➶

reach

Whether USP7 and USP47 directly interact with NLRP3 receptor or with other inflammasome component was not investigated.Enzymatic activity of UCHL5 (from the ubiquitin C‐terminal hydrolase family) is also increased after Salmonella enterica serovar Typhimurium infection, and UCHL5 silencing leads to impaired release of IL‐1β after infection 57.

31679183

UCHL5 affects INO80

| 1

UCHL5 activates INO80. 1 / 1

| 1

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reach

And finally, what genes are targeted by Uch37 containing INO80?

18922460

UCHL5 affects Hedgehog

| 1

UCHL5 activates Hedgehog. 1 / 1

| 1

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reach

The deubiquitinase UCHL5 and UCH37 positively regulates Hedgehog signaling by deubiquitinating Smoothened.

28992318

UCHL5 affects HMBS

| 1

UCHL5 inhibits HMBS. 1 / 1

| 1

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Most importantly, it was shown that loss of uchl5, the human orthologue of ubh-4, also increases UPS activity and the degradation of proteotoxic proteins in mammalian cells XREF_BIBR, thus further verifying the value of C. elegans as a model organism to evaluate the consequences of UPS modulation.

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UCHL5 affects Glioma

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In vitro analysis revealed that UCHL5 can inhibit migration and invasion of glioma cells mediated via a downregulation of SNRPF [142].

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UCHL5 affects Endometrial Neoplasms

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UCHL5 activates Endometrial Neoplasms. 1 / 1

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In conclusion, UCHL5 accelerated the growth of EC via the Wnt and beta-catenin pathway and was expected to be an attractive target for EC treatment.

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UCHL5 affects E2F1

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UCHL5 decreases the amount of E2F1. 1 / 1

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UCH37 depletion reduces the gene expression of both proliferative and pro apoptotic E2F1 target genes.

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UCHL5 affects Cyclin

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UCHL5 increases the amount of Cyclin. 1 / 1

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However, UCHL5 knockdown only blocked the expression of Cyclin D1 and CDK4 in A549 cells, suggesting that the effects of UCHL5 on cell cycle proteins is cell-type specific.

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UCHL5 affects Carcinogenesis

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Although previous studies have shown that UCHL5 promotes tumorigenesis , its role in lung cancer remains largely unknown .

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UCHL5 affects CDKN1A

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UCHL5 affects CDK4

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UCHL5 increases the amount of CDK4. 1 / 1

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However, UCHL5 knockdown only blocked the expression of Cyclin D1 and CDK4 in A549 cells, suggesting that the effects of UCHL5 on cell cycle proteins is cell-type specific.

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UCHL5 affects BAX

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UCHL5 inhibits BAX. 1 / 1

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UCHL5 affects Alzheimer Disease

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UCHL5 activates Alzheimer Disease. 1 / 1

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Of these hub proteins, UCHL5 in the proteasome associated module interacted with the histone acetyltransferase associated module, suggesting that UCHL5 causes a rupture between epigenetic transcriptional regulation and protein degeneration in AD.

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UCHL5 affects AR

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UCHL5 increases the amount of AR. 1 / 1

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We found that dual inhibitors of USP14 and UCHL5 such as b-AP15 [XREF_BIBR] and auranofin [XREF_BIBR] reduced AR protein level in both prostate and breast cancer cells.

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UCHL3 affects UCHL5

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UCHL3 increases the amount of UCHL5. 1 / 1

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This indicates that UCH-L5 protein levels are modulated by either a pathogen or a host, and only the activity of UCH-L3 is changed during infection with Salmonella, which could be caused by changes in post-translational modifications of this enzyme [XREF_BIBR].

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UBE3C affects UCHL5

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Modified UBE3C activates UCHL5. 1 / 1

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Other E3s may also mediate proteasome ubiquitination, as we found that overexpression of UbE3C enhances ubiquitination of Adrm1 and S5a but not Rpt5 and Uch37.

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TCF3 affects UCHL5

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TCF3 decreases the amount of UCHL5. 1 / 1

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biopax:msigdb

No evidence text available

SP1 affects UCHL5

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SP1 decreases the amount of UCHL5. 1 / 1

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biopax:msigdb

No evidence text available

RPN10 affects UCHL5

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RPN10 deubiquitinates UCHL5. 1 / 1

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PI3K_p85 affects UCHL5

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PI3K_p85 increases the amount of UCHL5. 1 / 1

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High glucose also increased UCHL5 protein expression, which was attenuated by LY294002, the dominant negative p85 and the dominant negative CREB.

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Nuclear factor related to kappa-B-binding protein affects UCHL5

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Nuclear factor related to kappa-B-binding protein activates UCHL5. 1 / 1

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Nuclear factor related to kappa-B-binding protein (NFRKB) is a part of this module and modulates the deubiquitinase activity of UCHL5 in the INO80 complex XREF_BIBR.

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MAZ affects UCHL5

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MAZ decreases the amount of UCHL5. 1 / 1

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biopax:msigdb

No evidence text available

LY294002 affects UCHL5

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LY294002 decreases the amount of UCHL5. 1 / 1

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High glucose also increased UCHL5 protein expression, which was attenuated by LY294002, the dominant negative p85 and the dominant negative CREB.

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K 7174 affects UCHL5

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K 7174 decreases the amount of UCHL5. 1 / 1

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ctd

No evidence text available

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ICG 001 affects UCHL5

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ICG 001 decreases the amount of UCHL5. 1 / 1

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ctd

No evidence text available

26191083

Heat-Shock Proteins affects UCHL5

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Heat-Shock Proteins activates UCHL5. 1 / 1

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| PMC

HSP90 affects UCHL5

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HSP90 activates UCHL5. 1 / 1

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| PMC

HNF1A affects UCHL5

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HNF1A decreases the amount of UCHL5. 1 / 1

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biopax:msigdb

No evidence text available

FOXN1 affects UCHL5

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FOXN1 decreases the amount of UCHL5. 1 / 1

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biopax:msigdb

No evidence text available

Enterolactone affects UCHL5

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Enterolactone increases the amount of UCHL5. 1 / 1

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ctd

No evidence text available

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Endometrial Neoplasms affects UCHL5

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Endometrial Neoplasms inhibits UCHL5. 1 / 1

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These results were opposite in UCHL5 knockdown EC cells.

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ELF2 affects UCHL5

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ELF2 decreases the amount of UCHL5. 1 / 1

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biopax:msigdb

No evidence text available

Cyclin affects UCHL5

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Cyclin decreases the amount of UCHL5. 1 / 1

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Furthermore, cyclin-dependent kinase 4/6 (CDK4/6) inhibition decreased UCHL5 expression, suppressed OTX015-R cell proliferation, and induced apoptosis.

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CREB affects UCHL5

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CREB increases the amount of UCHL5. 1 / 1

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High glucose also increased UCHL5 protein expression, which was attenuated by LY294002, the dominant negative p85 and the dominant negative CREB.

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CNTLN affects UCHL5

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CNTLN inhibits UCHL5. 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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Aroclor 1254 affects UCHL5

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Aroclor 1254 decreases the amount of UCHL5. 1 / 1

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ctd

No evidence text available

23650126

4-phenylbutyric acid affects UCHL5

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4-phenylbutyric acid increases the amount of UCHL5. 1 / 1

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ctd

No evidence text available

30980806

4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide affects UCHL5

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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide increases the amount of UCHL5. 1 / 1

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ctd

No evidence text available

27188386

17alpha-ethynylestradiol affects UCHL5

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17alpha-ethynylestradiol increases the amount of UCHL5. 1 / 1

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ctd

No evidence text available

23129252

(-)-epigallocatechin 3-gallate affects UCHL5

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(-)-epigallocatechin 3-gallate increases the amount of UCHL5. 1 / 1

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Analysis of the associated and non associated DUBs, such as UCHL2, USP14, UCH37, and UBC9 and DUB associated with core 20S proteasome (PSMD13) in RA-FLS showed that in the presence of IL-1beta, EGCG increased the expression of UCH37 and USP14, DUBs known to preferentially hydrolyze K48 linked polyubiquitin chains, with a marginal effect on unassociated DUB such as UCHL2 (XREF_FIG).

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3,3',4,4',5-pentachlorobiphenyl affects UCHL5

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3,3',4,4',5-pentachlorobiphenyl increases the amount of UCHL5. 1 / 1

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ctd

No evidence text available

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