USP14 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 14
HGNC Gene Symbol
USP14
Identifiers
hgnc:12612 NCBIGene:9097 uniprot:P54578
Orthologs
mgi:1928898 rgd:1311825
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP14
Number of Papers
284 retrieved on 2022-05-22

DepMap Analysis

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

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

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type
PLAA phospholipase A2 activating protein 0.39 0.39 2.04 2.10e-13
UBC ubiquitin C 0.286 BioGRID INDRA (1) Reactome (4)
BRAP BRCA1 associated protein -0.224 0.34 1.77 3.10e-10
USP15 ubiquitin specific peptidase 15 0.218 BioGRID INDRA (1) Reactome (4) 0.41 2.17 3.99e-15
ZMAT2 zinc finger matrin-type 2 0.198 -0.08 -0.51 2.35e-01
NUP50 nucleoporin 50 0.178 Reactome (2) -0.25 -1.46 8.06e-06
CERS5 ceramide synthase 5 0.171 -0.00 -0.10 9.78e-01

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP14using 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:0031965 nuclear membrane Cellular Component 1.33e-04 2.69e-02 7.89e-03

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP14 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
UBC ubiquitin C 7.94e-01 4.52e-34 9.98e-30
UBB ubiquitin B 3.04e-01 1.42e-07 1.56e-03

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 USP14 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP14 deubiquitinates DVL. 10 / 11
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Deubiquitination of Dishevelled by Usp14 is required for Wnt signaling.

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These data suggest that deubiquitination of Dvl by Usp14 is necessary for the interaction between Fzd and Dvl.

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Inhibition of USP14 increases Dvl polyubiquitination and significantly impairs downstream Wnt signaling.

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A recent report has shown that deubiquitination of disheveled (Dvl) by USP14 is required for Wnt signaling.

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Therefore, deubiquitination of Dvl by Usp14 may occur via their transient interaction during Wnt signal transduction.

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To test direct deubiquitination of Dvl by Usp14, we performed a ubiquitin chain trimming assay using immunopurified Dvl-ubiquitin conjugates and recombinant Usp14 in a proteasome-free condition (XREF_FIG and XREF_SUPPLEMENTARY).

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As a lack of Dvl deubiquitination by Usp14 appears to attenuate Wnt signaling, we proposed that an elevated forward rate of ubiquitination, which will be counteracted by Usp14 activity, might be induced by Wnt3a CM treatment.

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Effects of USP14 inhibitor IU1 confirmed that inhibition of USP14 by IU1 increases the K4 linked polyubiquitination of Dvl [XREF_BIBR].

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As inhibition of Usp14 activity increased Dvl polyubiquitination, we examined whether knockdown of Usp14 has any effect on Wnt signaling.

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Contrary to its established mechanistic role, Usp14 mediates deubiquitination of Dvl without a requirement for its UBL domain.
USP14 deubiquitinates CXCR4. 7 / 7
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These data suggest that the USP14 gene product indeed serves as a catalyst to deubiquitinate the CXCR4, because when its expression is reduced there is a reciprocal increase in CXCR4 ubiquitination.

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The physical interaction of CXCR4 and USP14 is paralleled by USP14 catalyzed deubiquitination of the receptor; knockdown of endogenous USP14 by RNA interference (RNAi) blocks CXCR4 deubiquitination, whereas overexpression of USP14 promotes CXCR4 deubiquitination.

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Co-localization of CXCR4 and USP14 also is time-dependent following CXCL12 stimulation.

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In summary, our findings demonstrate that CXCL12 activation of the CXCR4 leads to a dynamic ubiquitination and deubiquitination cycle and that USP14 preferentially interacts with and deubiquitinates CXCR4.

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Deubiquitination of CXCR4 by USP14 is critical for both CXCL12 induced CXCR4 degradation and chemotaxis but not ERK ativation.

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Deubiquitination of CXCR4 by USP14 would thus be expected to reduce the rate of ligand accelerated receptor degradation and result in an increased steady state level of receptors.

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Deubiquitination of CXCR4 by USP14 Is Critical for Both CXCL12 induced CXCR4 Degradation and Chemotaxis but Not ERK Activation *.
USP14 deubiquitinates AR. 6 / 6
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USP14 inhibits AR ubiquitination and subsequent degradation in both prostate and breast cancer cells [77, 78].

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In addition, reduction of UCHL5 by its siRNA did not affect the expression of AR, suggesting that USP14 but not UCHL5 recruited on the19S proteasome plays a selective role in the deubiquitination of AR.

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We found that IU1 and USP14 knockdown dramatically increased levels of ubiquitinated and K48 ubiquitinated AR, suggesting that USP14 is an AR DUB, capable of deubiquitinating and thereby stabilizing AR protein.

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Treatment of control MDA-MB-453 (either scramble shRNA or parental) cells with CHX for up to 12h caused decreased levels of AR, suggesting a contribution of AR protein synthesis to endogenous AR protein levels; however, co-treatment of CHX and USP14 shRNA or IU1 resulted more rapid decrease in levels of endogenous AR protein, strongly suggest that deubiquitination of AR protein by USP14 is essential for its protein stability.

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Additionally, both genetic and pharmacological inhibition of USP14 significantly suppressed cell proliferation in AR-responsive breast cancer cells by blocking G0/G1 to S phase transition and inducing apoptosis.

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Moreover, AR overexpression inhibited USP14 inhibition induced events, suggesting that AR deubiquitination by USP14 is critical for breast cancer growth and USP14 inhibition is a possible strategy to treat AR positive breast cancer.
USP14 deubiquitinates NLRC5. 5 / 5
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The ubiquitination of NLRC5 could be reversely regulated by USP14.

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In an effort to elucidate the mechanisms underlying this regulation, the Cui group showed that TLR4 stimulation activates the TRAF2/6 complex, which ubiquitinates NLRC5 on Lys1178 residue, presumably leading to its degradation and release of IKKalpha and IKKbeta to complex with IKKgamma [XREF_BIBR, XREF_BIBR] (XREF_FIG) This study also showed that the ubiquitin specific protease 14 (USP14) deubiquitinates NLRC5 to sustain the NLRC5 mediated inhibition of NF-kappaB activation.

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The researchers propose that, after the ubiquitination of NLRC5 at lysine 1178 is catalyzed by TRAF2/6, USP14 specifically removes the polyubiquitin chains from NLRC5 to enhance NLRC5-mediated inhibition of IKK–NF-κB signaling, thus forming a coherent feedforward loop to regulate IKK–NF-κB activation

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These results suggest that USP14 inhibits NLRC5 ubiquitination through its DUB activity.

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Next, we determined whether USP14 inhibited NLRC5 ubiquitination through its DUB activity.
USP14 leads to the deubiquitination of TAB2. 4 / 4
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Taken together, our data demonstrate that USP14 can negatively regulate autophagy induction by inhibiting Beclin 1 ubiquitination, interrupting association between TRAF6 and Beclin 1, and affecting TLR4-induced activation of NF-魏B through deubiquitination of TAB 2 protein

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Since USP14 induced the deubiquitination of TAB 2, we then examined the functional regulation of TLR4 mediated signaling in Ctrl and USP14 KD THP-1 cells.

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These results suggest that USP14 induces the deubiquitination of TAB 2.

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USP14 Induces Deubiquitination of TAB 2 and Inhibits TLR4 Mediated Signaling.
USP14 deubiquitinates BECN1. 3 / 3
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Based on these previous findings, we hypothesized that the suppression of Beclin 1 ubiquitination by USP14 might be critically associated with TRAF6 mediated ubiquitination in both autophagy and TLR4 mediated signaling.

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USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1

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The deubiquitination of BECLIN 1 by USP14 inhibits the PtdIns3P production of VPS34.
USP14 deubiquitinates CGAS. 2 / 2
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TRIM14 has been reported to interact with cGAS via its PRYSPRY domain and upon DNA virus infection recruit the proteasome-associated deubiquitinase (DUB) USP14 to deubiquitinate cGAS, preventing recruitment of p62 and autophagy-dependent degradation of cGAS (Jia et al., 2017) .

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TRIM14 has been reported to interact with cGAS via its PRYSPRY domain and upon DNA virus infection recruit the proteasome associated deubiquitinase (DUB) USP14 to deubiquitinate cGAS, preventing recruitment of p62 and autophagy dependent degradation of cGAS.
USP14 deubiquitinates FASN. 2 / 2
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As shown in Figure 4b,c, USP14 slightly reduced FASN ubiquitination.
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Since USP14 reduced FASN protein levels in cancer cells, it was necessary to confirm the deubiquitination of FASN by USP14.
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USP14 deubiquitinates Proteasome. 2 / 2
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Given that proteasome deubiquitination mediated by USP14 has fundamental roles in regulating proteasomal degradation of ubiquitinylated substrates XREF_BIBR XREF_BIBR, it is rational to speculate that perturbation of ubiquitin chain trimming functions of PfUSP14 may impact intraerythrocytic parasite development and cause difficulties for parasite egress from the host cell.

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USP14 deubiquitinates proteasome bound substrates that are ubiquitinated at multiple sites.
USP14 deubiquitinates CREBBP. 2 / 2
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To investigate whether USP14 deubiquitylated CBP, we transfected MLE12 cells to overexpress USP14 or treated them with IU1, and then we examined the ubiquitylation of CBP.

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Furthermore, we revealed that USP14 deubiquitylated CBP and promoted its stability.
USP14 deubiquitinates Proteasome on S26. 2 / 2
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Thus Uch37 and Usp14 may both deubiquitinate the 26S proteasome.

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Thus the DUB activities of Uch37 and/or Usp14 appear to antagonize ubiquitination of the 26S proteasome.
USP14 deubiquitinates VIM. 2 / 2
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Furthermore, USP14 can also deubiquitinate and stabilize vimentin, a vital protein which involves in epithelial-to-mesenchymal transition(EMT) and significantly promotes cell growth, migration and invasion in human gastric cancer

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According to the above results, USP14 de-ubiquitinates vimentin and increases its expression levels, which may influence the aggressiveness of GC cells.
Modified USP14 leads to the deubiquitination of CXCR4. 2 / 2
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The physical interaction of CXCR4 and USP14 is paralleled by USP14 catalyzed deubiquitination of the receptor; knockdown of endogenous USP14 by RNA interference (RNAi) blocks CXCR4 deubiquitination, whereas overexpression of USP14 promotes CXCR4 deubiquitination.

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Overexpression of USP14 promotes CXCR4 deubiquitination and allows it to escape degradation [XREF_BIBR, XREF_BIBR].
USP14 deubiquitinates ZUP1. 1 / 1
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Proteasomes function under tonic inhibitory conditions, possibly via the ubiquitin chain-trimming function of USP14, a proteasome-associated deubiquitinating enzyme (DUB).
USP14 leads to the deubiquitination of Proteasome on K48. 1 / 1
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We found that inhibition of USP14 accelerated the K48 ubiquitination and proteasome mediated degradation of AR protein.
USP14 leads to the deubiquitination of Wnt. 1 / 1
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Genetic and chemical suppression of USP14 activity caused an increase in Dishevelled (Dvl) polyubiquitination and significantly impaired downstream Wnt signaling, suggesting an oncogenic role for USP14 through Wnt and beta-catenin signaling enhancement [XREF_BIBR].
Modified USP14 leads to the deubiquitination of CREBBP. 1 / 1
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We found that overexpression of USP14 reduced CBP ubiquitylation, whereas IU1 had the opposite effect (XREF_FIG).
USP14 deubiquitinates DVL2. 1 / 1
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Usp14 deubiquitinates K63-linked polyubiquitin chains of Dvl

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Consequently, USP14 deficiency may cause ataxia in the ax J mice in part by perturbing the turnover and/or cell surface distribution of GABA A R. Still, since it is not clear that USP14 directly deubiquitinates GABA A R, it is also worth considering that this DUB may regulate the receptor indirectly.
USP14 deubiquitinates ELOVL6. 1 / 1
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Among the potential substrates identified, we show that fatty acid synthase (FASN), a key enzyme involved in hepatic lipogenesis, is a bona fide substrate of USP14.
USP14 deubiquitinates DDX58. 1 / 1
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n this study, we demonstrated USP14, a deubiquitinating enzyme, as a negative regulator in antiviral responses by directly deubiquitinating K63-linked RIG-I.
USP14 deubiquitinates BUR6. 1 / 1
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USP14 deubiquitinated this form of NCB1 at a rate comparable to that of wild-type conjugates, indicating that USP14 does not act obligatorily on ubiquitin-ubiquitin linkages (XREF_FIG).
USP14 deubiquitinates IKBKB. 1 / 1
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This study suggests that USP14 removes the ubiquitin chain of I-κB, therefore inducing I-κB degradation and increasing cytokine release in lung epithelial cells.
USP14 deubiquitinates GABBR1. 1 / 1
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Post-endocytotic Deubiquitination and Degradation of the Metabotropic γ-Aminobutyric Acid Receptor by the Ubiquitin-specific Protease 14
USP14 deubiquitinates CTNNB1. 1 / 1
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Additionally, DUBs USP14, USP15, USP47, and Fam/USP9X have been reported to prevent β-catenin turnover by inhibiting its Ub-proteasomal degradation
USP14 deubiquitinates AURKB. 1 / 1
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The Deubiquitinating Enzyme USP14 Regulates Leukemic Chemotherapy Drugs-Induced Cell Apoptosis by Suppressing Ubiquitination of Aurora Kinase B

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP14 affects Proteasome
2 | 3 43
USP14 inhibits Proteasome.
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1 | 2 26

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Previous studies reported that USP14 can inhibit the proteasome and protein turnover in cells XREF_BIBR.

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Our recent discovery of USP14 inhibitors clearly suggests that proteasomal DUBs can be valid pharmacological targets because USP14 inhibition may potentiate proteasome mediated protein quality control.

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USP14 as a component of proteasome-associated deubiquitinating enzyme complex can eliminate ubiquitins from proteasome-bound substrates and inhibit the proteasome non-catalytically ( Chen et al ., 2018 ) .

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USP14 negatively regulates proteasome activity by ubiquitin chain disassembly as well as by a noncatalytic mechanism XREF_BIBR - XREF_BIBR.

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USP14 is reversely associated with the proteasome to trim K48 Ub chains and negatively regulates proteasome activity.

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However, USP14 does not appear to strongly antagonize proteasome function in Xenopus extract, as treatment of extract with UbVS or the USP14 specific inhibitor IU1 did not appreciably enhance turnover of pre-ubiquitinated cyclin.

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Inhibition of USP14 activity reduced MNV-1 infection but WP1130 did not inhibit proteasome activity.

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Proteasome dysfunction induced by the loss of Usp14 results in a significant increase in the levels of phosphorylated tau in the brains of the ax J mice.

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To verify that Usp14 inhibits the proteasome in cells, we expressed Usp14 variants in usp14 -/- murine embryonic fibroblasts (MEFs), together with proteasome substrates.

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These results indicate that altered proteasome function caused by the loss of Usp14 results in widespread changes in the levels of activated stress kinases that have been implicated in tau phosphorylation.
Active USP14 inhibits Proteasome. 1 / 1
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We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro.
USP14 activates Proteasome.
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Accordingly , the inhibition of USP14 could improve the proteasome degradation activity [ 14 ] .

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Usp14 and Ubp6 can enhance the ATPase activity of the proteasome and partially open the CP gate [52,56-58].

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Loss of Ubp6 function, for example, increases aneuploidy tolerance in yeast, presumably due to an elevated proteasome capacity for turning over higher protein levels, and pharmacological inhibition of Usp14 in human cells has been shown to stimulate proteasome activity XREF_BIBR - XREF_BIBR.

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UBL domain of Usp14 and other proteins stimulates proteasome activities and protein degradation in cells.

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These results strongly suggest that the USP14 mediated proteasome activity regulation may be directly related to various human diseases including cancer.

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Recently, a small chemical compound (IU1) capable of inhibiting USP14 deubiquitination was shown to enhance proteasome mediated degradation of some substrates, including several proteins associated with neural degenerative diseases [XREF_BIBR].

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These USP14 specific aptamers effectively inhibited deubiquitinating activity and enhanced proteasome activity in vitro.

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Conversely, USP14 might also activate proteolysis by degrading ubiquitin chains on target proteins and thereby enhance gate opening of the 20S proteasome.

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Therefore, USP14 aptamers could be used to understand molecular mechanisms of USP14 activity and Ub homeostasis in cells.How to cite this article: Lee, J. H. et al. Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity.

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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.
USP14 bound to UBP6 activates Proteasome. 1 / 1
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This mutual interaction of USP14 and Ubp6 with the proteasome is thought to enhance selectivity of the proteasome for ubiquitinated proteins and couple deubiquitination to degradation.

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Recently, researches have revealed USP14 enhances cisplatin resistance through affecting Akt and ERK signaling pathways and accelerates cell proliferation and migration in GC.

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In addition, b-AP15, a novel inhibitor of USP14, selectively blocks the deubiquitylating activity of USP14, decreases viability and inhibits proliferation of MM cells, which is associated with growth [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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To explore the underlying mechanism by which USP14 promotes cell proliferation in LNcap cells, we monitored the cell cycle progression of each group exposed to various concentrations of IU1 (25, 50, 100muM) and found that inhibition of USP14 activity dramatically induced G0/G1 cell cycle arrest at different time points (0, 6, 12, 24, 48h) (XREF_FIG).

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Overexpression of USP14 promotes cell proliferation and migration, while down-regulation induces cell apoptosis and inhibits cell proliferation, migration, and invasion.

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We found that USP14 inhibition by shRNA significantly suppressed the proliferation of MDA-MB-231, MDA-MB-453, MDA-MB-468, HCC1937, and MCF7 breast cancer cell lines; however USP14 knockdown did not affect the proliferation of T47D cells, which could be related to the fact that these cells express very high levels of ER and very low levels of AR.

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Recently , researches have revealed USP14 enhances cisplatin resistance through affecting Akt / ERK signaling pathways and accelerates cell proliferation and migration in GC ( Fu et al ., 2018 ; Han K.H .

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USP14 was overexpressed in many cancers and promoted tumor cell proliferation through enhancing beta-catenin accumulation and inhibiting Bcl-xl-mediated cell apoptosis 11.

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Conversely, overexpression of USP14 induced increases in the protein level of cyclinD1and CDK6/4/2, the inactivation of Rb, and decreases in the expression of p27 and p15 (XREF_FIG), and led to increased proliferation of LNcap cells (XREF_FIG).

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USP14 promotes NSCLC cell proliferation, which may be associated with beta-catenin accumulation.

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These data suggest that knockdown of USP14 inhibits the proliferation and tumorigenesis in ESCC cells by suppressing and inhibiting the Wnt and beta-catenin signaling pathway.

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We found that (i) USP14 could bind to AR, and additionally, both genetic and pharmacological inhibition of USP14 accelerated the ubiquitination and degradation of AR; (ii) downregulation or inhibition of USP14 suppressed cell proliferation and colony formation of LNcap cells and, conversely, overexpression of USP14 promoted the proliferation; and (iii) reduction or inhibition of USP14 induced G0/G1 phase arrest in LNcap prostate cancer cells.

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Downregulation of USP14 Suppresses the Proliferation of ESCC Cells.

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The results demonstrated that downregulation of USP14 significantly inhibited the proliferation in EC109 (XREF_FIG) and TE10 cells (XREF_FIG).

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The downregulation of USP14 significantly inhibited breast cancer cell proliferation and metastasis.

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We also found that downregulation of USP14 significantly inhibited ESCC cell proliferation and ESCC tumor growth in nude mice.

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Knockdown of USP14 with the lentiviral vector delivery of shRNA in human hepatocarcinoma SMMC7721 cells suppressed cell proliferation, altered the cell cycle and induced cell apoptosis.

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Knockdown of Ubiquitin Specific Protease 14 (USP14) Inhibits the Proliferation and Tumorigenesis in Esophageal Squamous Cell Carcinoma Cells.

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Downregulation of USP14 significantly inhibited ESCC cell proliferation and ESCC tumor growth in nude mice.

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For example, Zhu et al. reported that expression of USP14 was increased in breast cancer tissues, and downregulation of USP14 significantly inhibited breast cancer cell proliferation and metastasis XREF_BIBR.
USP14 affects Ubiquitin
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USP14 inhibits Ubiquitin.
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USP14 impedes degradation of ubiquitinated proteins by removing ubiquitin chains from its substrates, while it could promote protein degradation via increasing proteasome activation.

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In agreement with this data, deletion of the mouse ortholog USP14 causes a depletion of free ubiquitin and ataxic mice (ax J) that contain a mutant form of the Usp14 gene display a reduction in free monoubiquitin levels in the brain.

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The deubiquitinating enzyme Usp14 allosterically inhibits multiple proteasomal activities and ubiquitin independent proteolysis.

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Hence, a more likely explanation for these genetic interactions between ubp6 Delta and the proteasome subunits is that association of Ubp6 with the mutant 26 S proteasomes stabilises these otherwise l[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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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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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] .

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However, later work has shown that ubiquitin overexpression does not correct the ax J deficits in hippocampal short term plasticity, and that transgenic expression of a catalytically inactive form of USP14 in the nervous system mimics the neuromuscular phenotype observed in the ax J mice, but causes a only a modest reduction of free ubiquitin.

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Similarly, UbVs were generated with high affinity for USP14, which inhibited Ub signaling and cell survival in yeast [XREF_BIBR].

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Ubiquitin specific protease-14 (USP14), a DUB reversibly associated with the proteasome, negatively regulates the activity of proteasomes by trimming ubiquitin chains on proteasome bound substrates.

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Taken together, these data show that phosphorylation of USP14 by Akt is important for this kinase to negatively regulate the UPS in a ubiquitin dependent manner.
USP14 bound to RPN1 inhibits Ubiquitin. 1 / 1
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The binding of USP14 to Rpn1 subunit through Ubl enhances its deubiquitinating activity, which is responsible for the removement of ubiquitin chains and prevent the release of ubiquitin to the proteolytic channel.
USP14 activates Ubiquitin.
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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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In yeast and mammals, loss of USP14 and Ubp6 results in increased degradation of ubiquitin and decreased levels of monomeric Ub, suggesting that one function of USP14 is to recycle ubiquitin at the proteasome [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

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Here we show that Usp14, a proteasome associated deubiquitinating enzyme, can inhibit the degradation of ubiquitin protein conjugates, in vivo and in vitro.

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These results strongly suggest that inhibition of USP14 by RNA aptamers might antagonize Ub chain-trimming on proteasomes, consequently facilitating the degradation of many UPS substrates.We investigated the effects of USP14 aptamers on HeLa cell viability.

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By regulating ubiquitin pools at the nerve terminal, Usp14 would therefore be able to modulate ubiquitin dependent processes required during synaptic development.

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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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In the UbAl bound form of Usp14, BL1 and BL2 are displaced, allowing the ubiquitin C-terminus access to the binding groove [71].

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Here we show that USP14, a proteasome associated deubiquitinating enzyme, can inhibit the degradation of ubiquitin protein conjugates both in vitro and in cells.

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USP14 prevents proteasomal degradation of ubiquitin.

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By separating ubiquitin from its conjugative target, Usp14 antagonizes this pathway of ubiquitin degradation.
USP14 increases the amount of Ubiquitin.
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USP14 increases the amount of Ubiquitin. 2 / 2
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Similarly, inhibition of USP14 alone by IU1 significantly increased the accumulation of polyubiquitinated proteins by 22.51 +/- 4.44% (P = 0.025, n = 5) and decreased the levels of monomeric ubiquitin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Free Ub, but not Ub conjugate, levels were reduced in the brain of ax J mice, but neuron specific expression of the Usp14 transgene was sufficient to restore free Ub levels in the spinal cord and motor neuron axons and could rescue ataxia phenotypes with defective neuromuscular junctions in ax J mice XREF_BIBR, XREF_BIBR.
Modified USP14 increases the amount of Ubiquitin. 2 / 2
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Biochemical analysis showed that the ubiquitin hydrolyase activity of this form of Usp14 is dependent on the presence of proteasomes, and neuronal expression of full-length Usp14 was able to restore the levels of monomeric ubiquitin in the brains of axJ mice.

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Analysis of spinal cord and sciatic nerve extracts from the ax J -Tg mice demonstrated that transgenic expression of Usp14 restored monomeric ubiquitin levels back to wt levels (XREF_FIG), indicating that Usp14 is required for the maintenance of monomeric ubiquitin in the spinal cord and motor neuron axons.
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We found that USP14 inhibition significantly induced apoptosis, as evident by PARP cleavage, and downregulation of the anti-apoptotic protein Bcl-2, in AR + / ER - breast cancer, and moderately induced apoptosis in AR + / ER + MCF7 cells.

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USP14 was discovered to negatively regulate cell apoptosis by interacting with Bcl-xl and upregulating its level.

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Additionally, AR overexpression inhibited cell apoptosis and growth suppression induced by USP14 silencing or IU1 treatment.

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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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Inhibition of USP14 causes G 0 / G 1 arrest and apoptosis in breast cancer cells.

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Flow cytometry revealed that the reduced expression of USP14 induced the apoptosis of the SKOV3 EOC cells.

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b-AP15, a small molecule inhibitor of two 19S regulatory-particle-associated deubiquitinases, USP14 and ubiquitin C-terminal hydrolase 5, could efficiently induce cell apoptosis or cell death in colorectal cancer cell line HCT116.24 In addition, b-AP15 can suppress the growth of FaDu squamous cell carcinoma cells.25 Our stratified survival analysis indicated that high USP14 expression could distinguish poor outcomes of patients with either early (TNM stage I-II) or advanced clinical stage (TNM stage III-IV), suggesting that USP14 may play a significant role throughout the development of ESCC.

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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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On the contrary, administration of b-AP15, a specific inhibitor of USP14, significantly increased leukemia cells apoptosis in a dose dependent manner.

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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.
Modified USP14 inhibits apoptotic process. 1 / 1
| 1

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Loss of USP14 expression and function dramatically decreased AR level, blocked G 0 / G 1 to S phase transition, and triggered cell apoptosis in AR + breast cancer cells, suggesting that targeting USP14/AR axis could be a potential strategy for TNBC therapy.
| 14

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However, this event was markedly abolished by ATG5 knockdown, subsequently restoring the cell proliferation in IR incubated OSCC cells.Finally, we found that USP14 mediated apoptosis was autophagy dependent in IR treated OSCC cells.

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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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Together, this confirmed that USP14 knockdown could resist OSCC cell apoptosis induced by b-AP15 treatment, which indicated that USP14 might be involved in b-AP15-induced apoptosis, further demonstrat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The combination of enzalutamide, a nonsteroidal antiandrogen, with either knockdown or pharmacological inhibition of USP14 promotes arrest of cell cycle progression and induces apoptosis (Xia et al. 2019).

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Interestingly, TgT by itself stimulated apoptosis, but only in adult cells.

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The PPAR-gamma agonist TgT attenuated MEHP mediated suppression of apoptosis and stimulation of oxidative metabolism by neonatal neutrophils.

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We previously confirmed that a specific USP14 and UCH37 inhibitor b-AP15 4 inhibited tumor cell growth and induced apoptosis and in vitro (data not shown).

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Selective USP14 and UCHL5 inhibitor b-AP15, induced apoptosis in MM cell lines and in primary MM cells via downregulation of cell division cycle 25C (CDC25C), CDC2, and cyclin-B1, as well as the activation of caspases and unfolded protein response pathways (p-IREalpha, p-eIF2alpha, and CHOP).

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The overexpression of USP14 in USP14 low expression cell lines promoted cell proliferation and migration, whereas USP14 downregulation suppressed tumor cell proliferation, decreased tumor cell colony number, increased apoptosis rate, and decreased cell migration and invasion.

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Additionally, both genetic and pharmacological inhibition of USP14 significantly suppressed cell proliferation in AR responsive breast cancer cells by blocking G 0 / G 1 to S phase transition and inducing apoptosis.
USP14 affects proteolysis
| 2 1 30
USP14 inhibits proteolysis.
| 2 18
| 2 18

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Thus, the presence of Usp14 on the 26S helps reduce wasteful ATP consumption and nonselective proteolysis.

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

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USP14 , one member of the ubiquitin-specific proteases DUBs family , is associated with the proteasome complex and inhibits proteolysis by catalyzing protein deubiquitination ( 14 ) .

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USP14 regulates proteasome activity and pharmacologic inhibition of USP14 increases the rate of protein degradation in the cell XREF_BIBR.

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Although present in Xenopus extracts (N.V.D., R.W.K., unpublished data), levels of USP14 associated with proteasomes in extract may be insufficient to impede proteolysis.

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These studies further confirmed two observations noted independently, i.e., (1) that inhibition of USP14 up-regulates proteasomal proteolysis in the cells from young donors, perhaps by virtue of 20S gate opening, but fail to do so in cells from the elderly, and (2) that inhibition of USP14 in T cells from both young and elderly donors influences the levels of poly-ubiquitinated proteins and free ubiquitin.

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Small molecule inhibitor of USP14, IU1, enhances proteasomal proteolysis of ubiquitinated substrate in T cells obtained from young but not those from elderly donors.

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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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Mouse embryonic fibroblasts lacking USP14 show enhanced clearance of several disease related proteins, including tau and polyglutamine expanded ataxin-3, and overexpression of catalytically inactive USP14 increases protein degradation [XREF_BIBR].

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Knockdown of USP2 or USP14 accelerated protein degradation of TNF-alpha, and abolished the effect of miR-124 on TNF-alpha protein stability.
USP14 activates proteolysis.
| 1 12
| 1 12

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Indeed, an inhibitor of the deubiquitinating enzyme Usp14 enhances proteasomal protein degradation and leads to the clearance of protein aggregates in human cells [XREF_BIBR].

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USP14 inhibition both by either drug like IU1 or siRNA silencing has been confirmed to accelerate protein degradation XREF_BIBR XREF_BIBR, which has also been confirmed in this report; USP14 silencing also affected CuPT induced GFPu protein degradation.

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SiRNA interference studies on the three DUBs in cancer cells suggested that RNAi of USP14 can inhibit cellular protein degradation [XREF_BIBR].

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Thus, therapeutic inhibition of USP14 may promote protein degradation through UPS and autophagy pathways simultaneously.

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Thus, Usp14 and Ubp6 appears to suppress protein degradation through three mechanisms : deubiquitination of proteasome substrates, the " noncatalytic effect, " which operates directly on the proteasom[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Usp14 activity antagonizes protein degradation.

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We found that a selective small-molecule inhibitor of USP14 stimulates protein degradation in vitro and in cells, and also attenuates toxic effects of oxidatively damaged proteins.

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We also found enhanced expression of transcripts encoding two ubiquitin specific proteases, including USP14 that suppresses protein degradation through deubiquitination of proteasome substrates, non catalytic inhibition of proteasome activity, and by regulating autophagy.

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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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The ability of USP14 to prevail over the proteasome in a kinetic competition may explain the suppression of protein degradation by USP14 's deubiquitinating activity 3.
Proteasome affects USP14
| 2 29
Proteasome deubiquitinates USP14.
| 15
Proteasome deubiquitinates USP14. 10 / 15
| 15

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Other inhibitors of the ubiquitin-proteasome system such as highly specific inhibitors of the proteasome associated deubiquitinating enzyme Usp14 could also show efficacy against aneuploid cells and thus could be used in the treatment of aneuploid cancers.

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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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The proteasome associated deubiquitinating enzyme Usp14 is essential for the maintenance of synaptic ubiquitin levels and the development of neuromuscular junctions.

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Tau degradation can also be promoted when deubiquitination by the proteasome associated deubiquitinating enzyme Usp14 is inhibited [XREF_BIBR].

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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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In ataxia (ax J) mice, profound neurological and synaptic defects result from a loss-of-function mutation in the proteasome associated deubiquitinating enzyme Usp14, which is required for recycling ubiquitin from proteasomal substrates.

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The proteasome associated deubiquitinating enzyme USP14 on one hand is functionally coupled with proteasomal activity and on the other hand a critical regulator of synaptic plasticity XREF_BIBR.

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ISG15 conjugation may also help direct modified proteins to the proteasome, because the proteasome-associated deubiquitinating enzyme (DUB), USP14, can recognize ISG15-modified substrates, or it may function to attract components of the ubiquitin conjugation machinery.ISG15 plays a role in resistance to Ebola virus (also VSV and rabies virus) by blocking the activity of Nedd4 via ISGylation (reviewed in Sadler and Williams, 2008).

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We report here that a small molecule selected for its capacity to inhibit the proteasome associated deubiquitinating enzyme Usp14 strongly enhances substrate degradation by the proteasome in cells.

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A recent and exciting study for example explored the proteasome associated deubiquitinating enzyme USP14 as a target for proteasome enhancement [XREF_BIBR].
Proteasome activates USP14.
| 2 8
| 2 8

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Still, USP14 activity can be remarkably enhanced by association with the proteasome -- up to ~ 800-fold -- suggesting its major regulatory role in proteasome function [XREF_BIBR, XREF_BIBR, XREF_BIBR].

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To confirm this, we tested TRIM11 on recombinant USP14 protein that were activated by proteasome enriched cell lysates or purified RPs.

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This suggests that a unique negative feedback model, in which USP14 is activated by proteasome and then proteasomal degradation is suppressed by deubiquitination, is the basis by which USP14 serves as a critical inhibitory component of the proteasome [ xref , xref , xref ].

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Indeed, phosphorylation of Usp14 (or the use of a Usp14 phosphomimetic) results in increased activity in assays with the fluorogenic substrate ubiquitin-7-amino-4-methylcoumarin (Ub-AMC), for both Usp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The resolution of this conundrum required the identification of a preferred substrate of Usp14 and of the properties that govern substrate preference.Cyclin B, ubiquitinated by its physiological ligas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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This suggests that a unique negative feedback model, in which USP14 is activated by proteasome and then proteasomal degradation is suppressed by deubiquitination, is the basis by which USP14 serves as a critical inhibitory component of the proteasome [XREF_BIBR, XREF_BIBR, XREF_BIBR].

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These results indicate that USP14 aptamer-induced proteasome activation might protect cells under various stressful conditions, including neurodegeneration.

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This is consistent with previous studies showing that PGJ2 lowers 26S proteasome levels and activity [XREF_BIBR, XREF_BIBR], and inhibits some of the thiol deubiquitinases including UCH-L1 and UCH-L3 [XREF_BIBR, XREF_BIBR], as well as Ub-isopeptidase activity [XREF_BIBR], but not USP14 as shown here in our current studies.

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XREF_FIG shows that free chains of diverse length and linkage type are all cleaved minimally by proteasome activated USP14, even upon long incubation.

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Again, this proteasome mediated USP14 activation was effectively prevented by recombinant TRIM11.
Proteasome inhibits USP14.
| 6
| 4

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By displacing USP14, TRIM11 changes proteasome composition and suppresses both catalytic and non catalytic effects of 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.

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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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Inhibition of USP14 by a small moleculeenhances proteasome activity and decreases misfolded proteins in mammalian cells following proteotoxic stress 11.
Proteasome inhibits USP14-W58A. 2 / 2
| 2

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Furthermore, proteasome inhibition or use of the mutant W58A USP14 facilitated the interaction of USP14 with the autophagy protein, GABARAP.

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Here we show that upon proteasome inhibition or expression of the mutant W58A USP14, association of USP14 with the 19S regulatory particle is disrupted.
USP14 affects AR
| 16
USP14 activates AR.
| 5
USP14 activates AR. 5 / 8
| 5

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Nevertheless, loss of USP14 reduced the volume of nuclear AR under DHT stimulation, which may result from the reduction of cellular AR after USP14 silencing.

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In addition, western blot analysis and immunofluorescent staining assay indicated that USP14 silencing significantly downregulated the abundance of AR in both the nucleus and cytoplasm under androgen stimulation, suggesting that cytosolic USP14 is not required for AR translocation and that USP14 silencing induced decrease of nuclear AR could be due to the decrease of total AR protein.

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Collectively, the results show that USP14 regulates the total AR level but not AR translocation, and mediates the responsiveness of AR + / ER - breast cancer to androgen.

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Our gene expression analyses of androgen responsive prostate cancer cells exposed to IU1 or USP14 siRNA show a downregulation of PSA but not AR mRNA expression, suggesting that USP14 might not enhance the transcriptional activity of AR.

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Thus we present a hypothesis that USP14 increases AR by inhibiting AR degradation, not by promoting AR transcription.
USP14 increases the amount of AR.
| 7
USP14 increases the amount of AR. 4 / 4
| 4

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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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We found that similar to USP14 shRNA, inhibition of USP14 by IU1 also significantly decreased AR protein level in breast cancer cells, supporting the conclusion that proteasomal DUB USP14 regulates the expression of AR in breast cancer cells.

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In the rescue experiments, IU1 induced AR downregulation can be reversed by proteasome inhibitor bortezomib (Velcade), suggesting that reduction of AR protein levels by the inhibition of USP14 depends on proteasome activity.

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Indeed, we found that inhibition or reduction of USP14 dramatically decreased the protein levels of AR and PSA (a target gene of AR).
Modified USP14 increases the amount of AR. 3 / 3
| 3

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Loss of USP14 expression and function dramatically decreased AR level, blocked G 0 / G 1 to S phase transition, and triggered cell apoptosis in AR + breast cancer cells, suggesting that targeting USP14/AR axis could be a potential strategy for TNBC therapy.

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Indeed, both pharmacological and genetic inhibition of USP14 markedly reduced, and conversely USP14 overexpression increased, the steady state protein levels of AR and its target gene PSA in LNcap cells (XREF_FIG).

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Conversely, overexpression of USP14 increased the expression of AR and PSA and decreased the expression of MDM2 and its phosphorylation (XREF_FIG).
USP14 inhibits AR.
| 4
USP14 inhibits AR. 3 / 4
| 3

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Hence, we proposed that inhibition or silence of USP14 induced AR downregulation is through enhancing the degradation of AR.

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We found that both IU1 and USP14 siRNA dramatically decreased the PSA mRNA but not the AR mRNA, indicating that USP14 inhibition or gene silence does not affect the transcription of AR (XREF_FIG).

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We therefore hypothesized that inhibition or silencing of USP14 could induce AR downregulation through enhancing AR degradation.
USP14 inhibits ubiquitinated AR. 1 / 1
| 1

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We found that IU1 and USP14 knockdown dramatically increased the ubiquitinated AR (XREF_FIG), suggesting that USP14 is a DUB for AR, capable of reversing the ubiquitination of AR and thereby stabilizing AR proteins.
USP14 affects autophagy
| 1 17
USP14 inhibits autophagy.
| 1 13
| 1 13

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In conclusion, the current investigation represents a new mechanism by which inhibition of USP14 triggers autophagy via ER stress mediated UPR in A549 cells.

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USP14 Negatively Regulates Autophagy Induction.

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According to this observation, it was shown that USP14 suppresses the activity of Beclin1 complex and induction of autophagy by interacting with and controlling K63- rather than K48 linked ubiquitin chains of Beclin1 [XREF_BIBR].

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Besides, the inhibition of USP14 by IU1-47 induced an increase of the autophagy flux, consistent with the increased degradation rate of Tau [XREF_BIBR].

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In addition, it has recently been reported that USP14 negatively regulates autophagy 34, which plays an important role in the regulation of hepatic TG metabolism.

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Ubiquitin-specific protease 14 promotes radio-resistance and suppresses autophagy in oral squamous cell carcinoma.

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Inhibition of USP14 induces ER stress mediated autophagy without apoptosis in lung cancer cell line A549.

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Moreover, we have for the first time demonstrated that the USP14 inhibition induces ER stress mediated autophagy in A549 cells by activation of c-Jun N-terminal kinase 1 (JNK1).

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Therefore, this study has demonstrated that typically inhibiting USP14 promotes autophagy in M1 like macrophages and alleviates CLP induced sepsis.

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USP14 Suppresses Autophagy by Cleaving Lys63-Ubiquitin Chains from BECLIN 1.
USP14 activates autophagy.
| 4
| 4

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Akt regulated USP14 activity can modulate both proteasomal degradation and autophagy through controlling K48 and K63 ubiquitination, respectively.

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Knockdown of USP14 or its inhibition with the inhibitor IU1 (see below Section 4.1) induces the activation of autophagy, indicating that USP14 is a negative regulator of autophagy in H4 (neuroglioma) cells.

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The deubiquitinating enzyme ubiquitin specific peptidase 14 (USP14) has been shown to modulate both proteasome activity and autophagy.

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The authors ascribed these phenotypes to TRIM14 's role in promoting cGAS stabilization and provide evidence that loss of TRIM14 allows for cGAS degradation via the E3 ligase USP14, which targets cGAS to p62 dependent selective autophagy.
USP14 affects cell cycle
| 1 14
USP14 activates cell cycle.
| 1 9
| 1 9

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In addition, silencing USP14 expression with siRNA or stable expression of shRNA also caused G0/G1 cell cycle arrest (XREF_FIG), indicating that USP14 promotes G1-S transition in androgen responsive prostate cancer cells.

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We confirmed that AR was highly expressed in the androgen responsive prostate cancer cells (LNcap cells) but was hardly detectable in the androgen-irresponsive prostate cancer cells (DU145 and PC3 cells) tested here (XREF_FIG), implying that the induction of cell cycle arrest by USP14 inhibition is AR dependent.

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It has been reported that USP14 expression was specifically upregulated in both lung adenocarcinoma cell lines and tumor tissues , and knockdown of USP14 expression significantly inhibited cell growth and cell cycle arrest in NSCLC cells12 .

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Furthermore, changes in key cell cycle regulators induced by the manipulation of USP14 function also support the notion that AR is a key target for USP14 in the prostate cancer cells.

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27 In this study, we have identified that USP14 promotes the cell cycle in prostate carcinoma cells by deubiquitination and stabilization of AR.

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It has been reported that USP14 expression was specifically upregulated in both lung adenocarcinoma cell lines and tumor tissues, and knockdown of USP14 expression significantly inhibited cell growth and cell cycle arrest in NSCLC cells XREF_BIBR.

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35 The AR dependent cell cycle arrest by inhibiting USP14 prompted us to investigate the interaction between USP14 and AR.

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It has been shown that USP14 modulates levels of key cell cycle regulatory proteins whose dysregulation is expected to affect the cell cycle [XREF_BIBR].

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USP14 promotes cell cycle by upregulating key proteins associated with the G0/G1 to S phase transition.

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To investigate the molecular mechanism by which USP14 promotes cell cycle, we performed western blot to detect several key proteins that are associated with G1-S phase transition.
USP14 inhibits cell cycle.
| 5
| 5

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To explore the underlying mechanism by which USP14 promotes cell proliferation in LNcap cells, we monitored the cell cycle progression of each group exposed to various concentrations of IU1 (25, 50, 100muM) and found that inhibition of USP14 activity dramatically induced G0/G1 cell cycle arrest at different time points (0, 6, 12, 24, 48h) (XREF_FIG).

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USP14 knockdown or treatment with USP14 inhibitor IU1 induced G0/G1 cell cycle arrest and suppressed cell proliferation in AR-positive and ER-negative breast cancer cells and androgen responsive prost[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Downregulation of USP14 expression arrested the cell cycle, which may be related to beta-catenin degradation.

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Inactivation of USP14 Perturbs Ubiquitin Homeostasis and Delays the Cell Cycle in Mouse Embryonic Fibroblasts and in Fruit Fly Drosophila.

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49, 50 Knocking-down of USP14 arrested cell cycle at G2/M phase.
AKT affects USP14
| 7 8
AKT activates USP14.
| 7 7
AKT activates USP14. 10 / 15
| 7 7

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Accordingly, when Usp14 is activated by AKT, the degradation of multiple proteins appears to be suppressed [74].

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The activation of Usp14 by AKT may provide a mechanism whereby growth signals can suppress catabolism through targeting proteasome activity.

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Thus, Akt not only activates USP14 by a different mechanism than the proteasome, but it can cooperate with the proteasome to achieve more aggressive removal of ubiquitin from proteasome-docked substrates.

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To validate Akt mediated activation of USP14 in cells, we coexpressed USP14 and Myr-Akt in HEK293T cells.

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Accordingly, when Usp14 is activated by AKT, the degradation of multiple proteins appears to be suppressed [74] .

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How does this relate to the observation that USP14 is activated by AKT?

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The notion that USP14 may serve as a focal point for regulating proteasome activity was consistent with a recent report that the kinase Akt activates USP14 via phosphorylation 35.

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Therefore, it remains unclear whether Ser432 phosphorylation generates a proteasome independent active form of Usp14.The activation of Usp14 by AKT may provide a mechanism whereby growth signals can s[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The notion that USP14 may serve as a focal point for regulating proteasome activity was consistent with a recent report that the kinase Akt activates USP14 via phosphorylation xref .

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Since USP14 is a negative regulator of the UPS and we found USP14 can be phosphorylated and activated by Akt, we reasoned that Akt mediated activation of USP14 might lead to inhibition of the UPS and generally enhance the stability of many proteins.
AKT inhibits USP14.
| 1
AKT inhibits USP14. 1 / 1
| 1

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From these results, we conclude that Akt negatively regulates the UPS in an USP14 dependent manner.
USP14 affects FASN
| 16
USP14 decreases the amount of FASN.
| 8
USP14 decreases the amount of FASN. 8 / 8
| 8

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Surprisingly, USP14 rather reduced the protein levels and activity of FASN in cancer cells, although it slightly inhibited the ubiquitination of FASN.
| PMC

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Therefore, these findings demonstrated that USP14 negatively regulates protein levels and activity of FASN in cancer cells.
| PMC

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USP14 Negatively Regulates the Levels and Activity of FASN in Cancer Cells.
| PMC

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In addition, USP14 overexpression reduced the FASN protein level in cancer cells (Figure 2b).
| PMC

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However, inhibition of both FASN and USP14 had no significant synergistic effect on cancer cell proliferation and, surprisingly, it was confirmed that USP14 negatively regulates the protein level and activity of FASN in cancer cells.
| PMC

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In LNCaP, MCF7 (human breast cancer cell), and A549 cell (human lung cancer cell), endogenous FASN protein levels were increased by USP14 knockdown contrary to the results in MPHs (Figure 2a).
| PMC

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Surprisingly, USP14 rather reduced the protein levels and activity of FASN in cancer cells, although it slightly inhibited the ubiquitination of FASN.

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In future studies, the investigation of alterations in the transduction pathway of USP14 and FASN using transcriptomic analysis is warranted to understand not only the interaction between the two proteins but also the correlation of the interactomes.Taken together, the results reveal that USP14 negatively regulates FASN levels unexpectedly in the cancer cells, and as a result, inhibition of USP14 was not conducive to cancer cell death through inhibition of FASN.
| PMC
USP14 activates FASN.
| 4
USP14 activates FASN. 4 / 4
| 4

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USP14 directly interacts with and increases FASN stability.

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Based on a previous finding that Usp14 is a novel DUB for FASN and enhances FASN stability by blocking proteasomal degradation in MPHs, we expected that a USP14 inhibitor IU1 could further reduce the activity of FASN by interfering with FASN stability when used together with a FASN inhibitor.
| PMC

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In addition to USP2a, which is well known as a DUB that regulates the level of FASN, a recent study showed that Usp14 significantly contributes to the development of hepatosteatosis by maintaining the stability of FASN in MPHs [7,20].
| PMC

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Recently, Liu et al. reported that Usp14 increases FASN stability in mouse primary hepatocytes (MPHs).
| PMC
USP14 inhibits FASN.
| 2
USP14 inhibits FASN. 2 / 2
| 2

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As a result, USP14 overexpression reduced enzymatic activity of FASN, whereas USP14 deficiency significantly increased FASN activity in cancer cells (Figure 3a,b).
| PMC

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This result further confirms that USP14 negatively regulates the protein level and the activity of FASN in cancer cells.
| PMC
USP14 increases the amount of FASN.
| 2
USP14 increases the amount of FASN. 1 / 1
| 1

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Inhibition of USP14 by IU1 or siRNAs targeting USP14 did not reduce FASN levels but rather increased FASN levels and activity in cancer cells.
| PMC
Modified USP14 increases the amount of FASN. 1 / 1
| 1

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As a result, overexpression of USP14 increased liver triglyceride contents and FASN protein levels.
USP14 affects Wnt
| 9
USP14 activates Wnt.
| 4
USP14 activates Wnt. 4 / 7
| 4

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Moreover, overexpression of USP14 in MM cell adhesion model could enhance the ability of cell adhesion by regulating Wnt signaling pathways, thereby promoting the CAM-DR in MM.

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This suggests that regulation of Wnt signaling by Usp14 is controlled at the level of Dvl, rather than downstream components such as beta-catenin.

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USP14 can enhance the signal transduction of Wnt and beta-catenin.

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Attenuation of Wnt signal transduction by Usp14 inhibition.
USP14 inhibits Wnt.
| 5
USP14 inhibits Wnt. 5 / 5
| 5

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These data suggest that knockdown of USP14 inhibits the proliferation and tumorigenesis in ESCC cells by suppressing and inhibiting the Wnt and beta-catenin signaling pathway.

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Downregulation of USP14 Suppresses the Activation of Wnt and beta-Catenin Signaling Pathway in ESCC Cells.

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Increased Wnt reporter activity upon ectopic expression of Dvl, but not beta-catenin, was reduced by expression of Usp14-CA (XREF_FIG).

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Accordingly, transient overexpression of Usp14-CA reduced Wnt reporter activity (XREF_SUPPLEMENTARY).

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Depletion of Usp14 attenuated downstream Wnt signalling which was further evidenced when correlation between the levels of Usp14 and beta-catenin in colon tissues was observed.
USP14 affects NFkappaB
| 9
USP14 inhibits NFkappaB.
| 7
| 7

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Next, we tested whether USP14 also enhanced NLRC5 mediated inhibition of TRAF2/6 independent noncanonical NF-kappaB signaling.

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Furthermore, USP14 was also found to inhibit the RIG-I-triggered NF-kappaB activation by deubiquitinating K63 linked RIG-I.

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These results suggest that USP14 specifically enhanced NLRC5 mediated inhibition of NF-kappaB activation through the inhibition of NLRC5 ubiquitination via its DUB activity.

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Because USP14 specifically enhanced NLRC5 mediated inhibition of NF-kappaB activation, we reasoned that USP14 deficiency would result in the accumulation of ubiquitinated NLRC5 and increased NF-kappaB activation under physiological conditions.

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We found that overexpression of USP14 in 293/TLR4 cells suppressed NF-kappaB activity through TLR4 stimulation.

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These results suggest that USP14 inhibits NF-kappaB signaling in an NLRC5 dependent manner.

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In this study, we aimed to clarify the role of the USP14-NLRC5 pathway in wear particle induced osteolysis in vitro and in vivo We found that NLRC5 or USP14 overexpression inhibits titanium particle induced proinflammatory tumor necrosis factor alpha (TNF-alpha) production and NF-kappaB pathway activation, and also decreases M1 macrophage polarization and PI3K and AKT pathway activation.
USP14 activates NFkappaB.
| 2
| 2

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Conversely, USP14 KD THP-1 cells clearly enhanced NF-kappaB activation and the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta.

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Based on these results, USP14 can induce the activation of NF-kappaB and regulate the up-regulation of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-18 (IL-18) expression by activating the NF-kappaB signal pathway.
USP14 affects NLRC5
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USP14 inhibits NLRC5.
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USP14 inhibits NLRC5. 4 / 5
| 4

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Next, we tested whether USP14 also enhanced NLRC5 mediated inhibition of TRAF2/6 independent noncanonical NF-kappaB signaling.

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Because USP14 specifically enhanced NLRC5 mediated inhibition of NF-kappaB activation, we reasoned that USP14 deficiency would result in the accumulation of ubiquitinated NLRC5 and increased NF-kappaB activation under physiological conditions.

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These results suggest that USP14 specifically enhanced NLRC5 mediated inhibition of NF-kappaB activation through the inhibition of NLRC5 ubiquitination via its DUB activity.

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These results suggest that USP14 inhibits NF-kappaB signaling in an NLRC5 dependent manner.
USP14-C114A inhibits NLRC5. 1 / 1
| 1

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USP14 (C114A) also failed to enhance the inhibitory effect of NLRC5 on MyD88 induced NF-kappaB activation (XREF_FIG).
USP14 activates NLRC5.
| 4
USP14 activates NLRC5. 4 / 4
| 4

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USP14 modulates NLRC5 function through its DUB activity.

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Higher intrinsic USP14 levels in BMMs compared with BMDCs " forced " BMMs to move toward a state of higher USP14 values and subtly raised the sensitivity to NLRC5 in BMMs.

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In contrast, ubiquitin specific protease 14 (USP14) specifically removes the polyubiquitin chains from NOD like receptor family CARD domain containing 5 (NLRC5) and thereby enhances the NLRC5 mediated inhibition of NF-kappaB signaling.

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USP14 deficiency significantly attenuates the inhibitory ability of NLRC5 on NF-kappaB activation, whereas the K1178R NLRC5 mutant showed similar inhibition of NF-kappaB activity in both WT and USP14 KO cells.
USP14 affects USP14
| 1 4
USP14 inhibits USP14.
| 1 1
USP14 inhibits USP14. 2 / 3
| 1 1

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PtPT is also strikingly distinct from IU1, a USP14 inhibitor reported previously [ xref ], which inhibits USP14 but not UCHL5 activity and promotes the degradation of ubiquitinated proteins.

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We found that (i) USP14 could bind to AR, and additionally, both genetic and pharmacological inhibition of USP14 accelerated the ubiquitination and degradation of AR; (ii) downregulation or inhibition of USP14 suppressed cell proliferation and colony formation of LNcap cells and, conversely, overexpression of USP14 promoted the proliferation; and (iii) reduction or inhibition of USP14 induced G0/G1 phase arrest in LNcap prostate cancer cells.
USP14 activates USP14.
| 1
USP14 activates USP14. 1 / 3
| 1

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Furthermore, we found that NCOA4 was upregulated by ubiquitin specific peptidase 14 (USP14) via a deubiquitination process in damaged neurons, and we found evidence of pharmacological inhibition of USP14 effectively reducing NCOA4 levels to protect neurons from ferritinophagy-mediated ferroptosis.
USP14 decreases the amount of USP14.
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USP14 decreases the amount of USP14. 2 / 2
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USP14 siRNA effectively suppressed expression of USP14 without affecting that of off target protein, p38.

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Another example of neuroprotection was found in stroke, in which decreased expression of USP14 by microRNA or miR-124, as well as USP14 inactivation, was linked to neuron survival in the post-ischemic mouse brain 69.
TRIM11 affects USP14
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TRIM11 inhibits USP14.
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TRIM11 inhibits USP14. 3 / 3
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11) strongly reduced the deubiquitinase activity in the control lysates, and rendered TRIM11 ineffective in reducing deubiquitinase activity, indicating that TRIM11 specifically inhibits the deubiquitinase activity of USP14.

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By displacing USP14, TRIM11 changes proteasome composition and suppresses both catalytic and non catalytic effects of USP14.

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Together, these results show that TRIM11 inhibits the association of USP14 with PSMD2, preventing it from docking on the proteasome.
TRIM11 activates USP14.
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TRIM11 activates USP14. 3 / 3
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TRIM11 activates the proteasome and promotes overall protein degradation by regulating USP14.

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Together, these results demonstrate that TRIM11 enhances cell survival and proliferation and suppresses apoptosis by inhibiting USP14.

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TRIM11 relieves the inhibition of USP14 on the proteasome.
TRIM11 increases the amount of USP14.
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TRIM11 increases the amount of USP14. 2 / 2
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In contrast, the amounts of USP14 were decreased in the pellets and conversely increased in the detergent-soluble SN, consistent with its displacement from the proteasome by TRIM11.

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TRIM11 abrogated the inhibitory effect of USP14 overexpression on YFP-CL1 in both unstressed and heat stressed cells.
USP14 affects cell growth
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USP14 activates cell growth.
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It has been reported that USP14 expression was specifically upregulated in both lung adenocarcinoma cell lines and tumor tissues, and knockdown of USP14 expression significantly inhibited cell growth and cell cycle arrest in NSCLC cells XREF_BIBR.

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As shown in XREF_FIG, USP14 inhibition or silence failed to induce apoptosis or PARP cleavage but instead induced moderate decreases of p53 and Bax, suggesting that cell growth suppression mediated by USP14 inhibition or silence is through promoting cell proliferation, independent of cell death.

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USP14 inhibition via administration of IU1 or USP14 specific siRNA and shRNA enhanced cell growth inhibition and apoptosis induction by enzalutamide in breast cancer cell lines in vitro and in vivo.

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Since we have observed that inhibition or knockdown of USP14 inhibited cell growth in LNcap cells, we further investigated whether USP14 inhibition or silence induces cell death of LNcap cells by measuring Annexin V-FITC and PI-positive cells with flow cytometry and by measuring PARP cleavage and p53 and Bax protein expression with western blot analyses.

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It has been reported that USP14 expression was specifically upregulated in both lung adenocarcinoma cell lines and tumor tissues , and knockdown of USP14 expression significantly inhibited cell growth and cell cycle arrest in NSCLC cells12 .
USP14 inhibits cell growth.
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We previously confirmed that a specific USP14 and UCH37 inhibitor b-AP15 4 inhibited tumor cell growth and induced apoptosis and in vitro (data not shown).

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Since we have observed that inhibition or knockdown of USP14 inhibited cell growth in LNcap cells, we further investigated whether USP14 inhibition or silence induces cell death of LNcap cells by measuring Annexin V-FITC/PI-positive cells with flow cytometry and by measuring PARP cleavage and p53 and Bax protein expression with western blot analyses.
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To investigate the molecular mechanism by which USP14 promoted proliferation and invasion in ESCC cells, we examined the effects of USP14 on the activation of the Wnt and beta-catenin signaling pathway.

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In addition, IU1, a small-molecule inhibitor of USP14, accelerated the degradation of a subset of proteasome substrates and suppressed cell proliferation, migration, and invasion in lung cancer and cervical cancer.

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USP14 depletion or its specific inhibitor IU1 treatment decreased cell proliferation , invasion , migration , and Vascular Mimicry ( VM ) formation even under hypoxia conditions in HCC cell lines .

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Overexpression of USP14 could enhance proliferation, prevent apoptosis and promote invasion and migration of PDAC cells.

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The overexpression of USP14 in USP14 low expression cell lines promoted cell proliferation and migration, whereas USP14 downregulation suppressed tumor cell proliferation, decreased tumor cell colony number, increased apoptosis rate, and decreased cell migration and invasion.

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Downregulation of USP14 also suppressed the migration and invasion in ESCC cells.

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Downregulation of USP14 Suppresses the Migration and Invasion of ESCC Cells.
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USP14 inhibits Cell Survival.
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Knock-down of USP14 in multiple myeloma cells induces loss of cell viability.

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Similarly , UbVs were generated with high affinity for USP14 , which inhibited Ub signaling and cell survival in yeast [ 106 ] .

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Similarly, UbVs were generated with high affinity for USP14, which inhibited Ub signaling and cell survival in yeast [XREF_BIBR].

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USP14 and UCHL5 short interfering RNA knockdown decreases MM cell viability.
USP14 activates Cell Survival.
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However, USP14 over-expression significantly promoted the cell viability of OSCC cells after IR treatment.

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The MTT assay showed that USP14 overexpression increased the cell viability in BGC-823 and MGC-803 cells, and the knockdown of USP14 repressed the cell viability in BGC-823 and MGC-803 cells.

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As shown in Figure XREF_FIG, pharmacological inhibition of USP14 caused dose dependent inhibition of cell viability in endometrial cancer cell lines with an IC 50 of 181.3 and 117.5 nM for HEC155 (left panel) and ECC1 (right panel), respectively.
USP14 affects MAPT
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USP14 inhibits MAPT.
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USP14 inhibits MAPT. 3 / 3
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The DUB USP14 suppresses turnover of Tau and TDP-43 in mouse embryonic fibroblasts (MEFs) by impairing the protea-some; therefore, small-molecule inhibitors of USP14 could help clear these toxic proteins from cells.

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USP14 aptamers enhanced tau degradation in cultured cells and protected against oxidative stress.

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In conclusion, pharmacologically inhibiting (with low or high IU1 concentrations) or genetically down-regulating USP14 fail to enhance proteasomal degradation of Ub-proteins or Tau in neurons.
USP14 activates MAPT.
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USP14 activates MAPT. 3 / 3
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192 Conversely, IU1, a small molecule inhibitor of USP14, stimulated the degradation of tau.

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This result is also consistent with Boselli et al.’s observation that USP14 inhibition enhances tau degradation in cultured neurons [213].
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Intriguingly, Lee et al. demonstrated that IU1, a selective small-molecule inhibitor of USP14, accelerated proteasomal degradation of tau and TDP-43, which have been implicated in neurodegenerative diseases XREF_BIBR.
USP14 increases the amount of MAPT.
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USP14 increases the amount of MAPT. 1 / 1
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The DUB USP14 suppresses turnover of Tau and TDP-43 in mouse embryonic fibroblasts (MEFs) by impairing the protea-some;
USP14 affects CTNNB1
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USP14 activates CTNNB1.
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USP14 activates CTNNB1. 1 / 3
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USP14 can enhance the signal transduction of Wnt and beta-catenin.
USP14 inhibits CTNNB1.
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USP14 inhibits CTNNB1. 2 / 2
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These data suggest that knockdown of USP14 inhibits the proliferation and tumorigenesis in ESCC cells by suppressing and inhibiting the Wnt and beta-catenin signaling pathway.

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Downregulation of USP14 Suppresses the Activation of Wnt and beta-Catenin Signaling Pathway in ESCC Cells.
USP14 decreases the amount of CTNNB1.
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USP14 decreases the amount of CTNNB1. 2 / 2
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Our study showed that downregulation of USP14 decreased the protein expression levels of beta-catenin, cyclin D1, and c-Myc in ESCC cells.

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Mechanically, downregulation of USP14 decreased the protein expression levels of beta-catenin, cyclin D1, and c-Myc in ESCC cells.
Aur affects USP14
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Aur inhibits USP14. 6 / 6
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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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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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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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Molecularly, Aur inhibits 19S-associated DUBs USP14 and UCHL5 [ xref , xref ].
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Ubiquitin specific protease 14 (USP14) promotes proliferation and metastasis in pancreatic ductal adenocarcinoma.

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30 Overall, these data suggest that increased expression of Usp14 may enhance beta-catenin-mediated transformation of normal colon cells, but not metastasis of malignant colon cancer cells.

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In contrast, studies using OSCC cells have demonstrated that TGF-beta signals can mediate Epithelial- mesenchymal transitions, further contributing to cancer cells migration and invasion (Meng et al.,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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For example, Zhu et al. reported that expression of USP14 was increased in breast cancer tissues, and downregulation of USP14 significantly inhibited breast cancer cell proliferation and metastasis XREF_BIBR.

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The downregulation of USP14 significantly inhibited breast cancer cell proliferation and metastasis.
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Over-expression of a catalytically inactive form of USP14 rescues the PPF deficit and restores synaptic vesicle number, indicating that USP14 regulates presynaptic structure and function independently of its role in deubiquitination.

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To determine whether the BALBnmf375 mice were also resistant to the PPF deficit caused by USP14 deficiency in the C57ax J mice, we analyzed PPF in the CA1 region of the nmf375 hippocampus.

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On the other hand, restoration of proteasomal activity and hence expression of USP14 and presynaptic proteins rescued PPF in SPL fl/fl/Nes mice.

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XREF_BIBR a reduction in the deubiquitinating enzyme USP14 impairs PPF without changing the initial release probability.
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Finally, the PPF deficit caused by loss of USP14 can be rescued by pharmacological inhibition of proteasome activity, suggesting that inappropriate protein degradation underlies the PPF impairment.

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Although PPF is usually inversely related to release probability, USP14 deficiency impairs PPF without altering basal release probability.
USP14 affects MDM2
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USP14 decreases the amount of MDM2.
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