UCHL1 Data Analysis

HGNC Gene Name
ubiquitin C-terminal hydrolase L1
HGNC Gene Symbol
UCHL1
Identifiers
hgnc:12513 NCBIGene:7345 uniprot:P09936
Orthologs
mgi:103149 rgd:3928
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for UCHL1
Number of Papers
1592 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

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with UCHL1using 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

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out UCHL1 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
ANKRD1 ankyrin repeat domain 1 3.41e-01 5.45e-05 4.75e-02
ANKRD11 ankyrin repeat domain 11 4.29e-01 5.87e-05 4.75e-02
CEP350 centrosomal protein 350 7.40e-01 6.41e-05 4.75e-02
FNBP1 formin binding protein 1 7.55e-01 6.03e-05 4.75e-02
H4C8 H4 clustered histone 8 8.95e-01 2.97e-05 4.75e-02
HSPA9 heat shock protein family A (Hsp70) member 9 4.45e-01 3.63e-05 4.75e-02
PRC1 protein regulator of cytokinesis 1 5.09e-01 2.59e-05 4.75e-02
SASH1 SAM and SH3 domain containing 1 7.82e-01 1.94e-05 4.75e-02
SMC1A structural maintenance of chromosomes 1A 5.68e-01 1.47e-05 4.75e-02
CLINT1 clathrin interactor 1 6.09e-01 7.77e-05 4.94e-02
HMGB2 high mobility group box 2 3.87e-01 8.14e-05 4.94e-02

Gene Set Enrichment Analysis

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

Literature Mining

INDRA was used to automatically assemble known mechanisms related to UCHL1 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
UCHL1 deubiquitinates NOX4. 10 / 12
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UCH-L1 restores H 2 O 2 -generating activity of NOX4 by deubiquitinating NOX4.

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We further investigated whether endogenous NOX4 is also deubiquitinated by UCH-L1 in B16F10 cells.

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We further showed that UCH-L1 increases ROS levels in HUVEC by deubiquitinating NOX4 in VEGF signaling.

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These immunoprecipitation studies confirm that UCH-L1 deubiquitinates NOX4 in HUVECs, and suggest that UCH-L1 is involved in ROS mediated angiogenesis in HUVECs by modulating NOX4 activity via deubiqu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Fig. 4 B shows that ubiquitination of NOX4 was markedly decreased by adding back of control UCH-L1 in UCH-L1-knocked down HUVECs.

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Immunoprecipitation studies confirmed that UCH-L1 deubiquitinates NOX4, suggesting that UCH-L1 might be involved in H 2 O 2 -mediated cell invasion by regulating the NOX4 activity through deubiquitination.

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Also, we demonstrated that UCH-L1 restores H 2 O 2 -gernerating activity of NOX4 by deubiquitinating NOX4.

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On the other hand, NOX4 overexpressed in HeLa cells happens to be ubiquitinated, and NOX4 following deubiquitination by UCH-L1, restored H2O2 generating activity.

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These findings indicate that H2O2 levels regulated by UCH-L1 are necessary for cell invasion to occur and demonstrate that UCH-L1 promotes cell invasion by up-regulating H2O2 via deubiquitination of NOX4.

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Because H 2 O 2 generating activity of NOX4 is negatively modulated by ubiquitination and UCH-L1 promotes ROS induced cell invasion and migration in HeLa cells by deubiquitinating the NOX4 [13], we in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
UCHL1 deubiquitinates TP53. 6 / 6
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However, while exploring the relationship between UCH-L1 and p53 ubiquitination, it is important to keep in mind that, despite hypotheses to the contrary [XREF_BIBR, XREF_BIBR], it is unlikely that UCH-L1 directly deubiquitinates or ubiquitinates p53 based on what is known about UCH-L1 structure and function [XREF_BIBR, XREF_BIBR].

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These results indicate that UCHL1 could deubiquitinate p53 and p14(ARF) and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor.

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These results indicate that UCHL1 could deubiquitinate p53 and p14(ARF)

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These results indicate that UCHL1 could deubiquitinate p53 and p14 (ARF) and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor.

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Our previous work demonstrated that UCHL1 could activate the p14ARF-p53 signaling pathway by deubiquitinating p53 and p14ARF as well as ubiquitinating MDM2, which might be through its two opposing enzyme activities, hydrolase and ligase, further resulting in its tumor suppressive role in NPC tumorigenesis XREF_BIBR, XREF_BIBR.

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As P53 protein is regulated through ubiquitin dependent degradation in tumorigenesis, UCHL1 promotes p53 signaling by deubiquitinating p53 and p14 ARF and ubiquitinating MDM2 for further MDM2 degradation and p53 stabilization, thus involved in NPC pathogenesis as a functional TSG XREF_BIBR.
UCHL1 deubiquitinates NTRK2. 5 / 5
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We provide evidence that UCH-L1 can deubiquitinate TrkB directly.

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Together, our results suggest that the ubiquitination of TrkB is a mechanism that controls its downstream signaling pathways via the regulation of its endocytosis and postendocytic trafficking and that UCH-L1 mediates the deubiquitination of TrkB and could be a potential target for the modulation of hippocampus dependent memory.

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UCH-L1 mediates the deubiquitylation of TrkB by cleaving ubiquitin (probably polyubiquitin chains) and thereby inhibits TrkB degradation.

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Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB

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Deubiquitination of TrkB by the DUB UCHL1 has been reported, which maintains expression of the receptor on the cell surface [XREF_BIBR].
UCHL1 deubiquitinates CDKN2A. 4 / 4
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As P53 protein is regulated through ubiquitin dependent degradation in tumorigenesis, UCHL1 promotes p53 signaling by deubiquitinating p53 and p14 ARF and ubiquitinating MDM2 for further MDM2 degradation and p53 stabilization, thus involved in NPC pathogenesis as a functional TSG XREF_BIBR.

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Our previous work demonstrated that UCHL1 could activate the p14ARF-p53 signaling pathway by deubiquitinating p53 and p14ARF as well as ubiquitinating MDM2, which might be through its two opposing enzyme activities, hydrolase and ligase, further resulting in its tumor suppressive role in NPC tumorigenesis XREF_BIBR, XREF_BIBR.

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These results indicate that UCHL1 could deubiquitinate p53 and p14 (ARF) and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor.

trips
These results indicate that UCHL1 could deubiquitinate p53 and p14(ARF) and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor.
UCHL1 deubiquitinates EGFR. 3 / 3
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UCHL1 inhibits EGFR ubiquitination and degradation.

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UCHL1 deubiquitinates epidermal growth factor receptor, preventing its degradation and resulting in the activation of multiple downstream signaling cascades that positively regulate cardiac hypertrophy.

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In addition, knockdown of UCHL1 increased EGFR polyubiquitination and decreased the EGFR level with or without EGF stimulation.
UCHL1 deubiquitinates HIF1A. 3 / 3
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We revealed that UCHL1 directly interacts with HIF-1α, mediates the deubiquitination of HIF-1α, and upregulates HIF-1 activity through the stabilization of HIF1α

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UCHL1 deubiquitinates HIF-1alpha protein and upregulates HIF-1 activity in murine breast cancer derived EMT6 cells.

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Moreover, when the ubiquitination status of the HIF-1alpha protein was directly evaluated by performing immunoprecipitation assays, the knockdown of endogenous UCHL1 significantly increased HIF-1alpha ubiquitination (XREF_FIG and XREF_SUPPLEMENTARY).
UCHL1 deubiquitinates CD36. 2 / 2
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Deubiquitination of CD36 by UCHL1 promotes foam cell formation.

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Deubiquitination of CD36 by UCHL1 promotes foam cell formation.
UCHL1 deubiquitinates SNCA. 2 / 2
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The deubiquitination of α-synuclein aggregates by USP9X favor their degradation by autophagy, while UCH-L1 contribute to the accumulation of α-synuclein by downregulating its lysosomal degradation.

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No clear substrates have been described for UCHL1 in vivo, but UCHL1 may deubiquitinate alpha-synuclein.
UCHL1 leads to the deubiquitination of VEGF. 1 / 1
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We further showed that UCH-L1 increases ROS levels in HUVEC by deubiquitinating NOX4 in VEGF signaling.
UCHL1 deubiquitinates SLC5A7. 1 / 1
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These data provide novel and potentially important evidence that UCHL1 may play a role in the regulation of cholinergic function by affecting CHT ubiquitination and degradation.
UCHL1 deubiquitinates TGFBR1. 1 / 1
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Besides, we found that recombinant UCHL1 protein is able to deubiquitinate TβRI and SMAD2 in vitro directly, and N-ethylmaleimide (NEM) treatment blocked this process by inhibiting UCHL1 DUB activity
UCHL1 deubiquitinates CXCL8. 1 / 1
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It was showed that UCH-L1 over-expression inhibited NF-κB activation and decrease IL-6 and IL-8 levels, while knockdown of it enhanced NF-κB activation and increase IL-6 and IL-8 levels during TNF-α treatment.
UCHL1 deubiquitinates MAPT. 1 / 1
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Our results suggest that UCH-L1 may be associated with hippocampal MSF followed the epileptogenesis through mediating phosphorylation of tau.
Modified UCHL1 leads to the deubiquitination of EGFR. 1 / 1
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As expected, overexpression of UCHL1 (WT) significantly abrogated EGFR ubiquitination and increased EGFR levels, whereas this effect was reversed by UCHL1 (C90S; XREF_FIG).
UCHL1 deubiquitinates tyrosine-phosphorylated SNCA on lysine. 1 / 1
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UCHL1 deubiquitinates SMAD2. 1 / 1
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We also found that UCH-L1 interacts, deubiquitinates, and stabilizes SMAD2 and SMAD3.
UCHL1 deubiquitinates SNCA phosphorylated on S129 and tyrosine on lysine. 1 / 1
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UCHL1 deubiquitinates UCHL1. 1 / 1
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Interestingly, UCH-L1 catalyzes its own deubiquitination in an intramolecular manner, thereby regulating the lifetime of this modification.
UCHL1 deubiquitinates RPTOR. 1 / 1
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UCHL1 deubiquitinates Raptor, thereby destabilizing mTORC1 complex formation and shifting the balance toward mTORC2 dependent signaling.
UCHL1 leads to the deubiquitination of HSPA5. 1 / 1
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Downregulation of UCHL1 by UCHL1 siRNA decreased poly-ubiquitination of GRP78.
UCHL1 deubiquitinates BACE1. 1 / 1
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Whether UCHL1, with its physically constrained catalytic site, can deubiquitinate BACE1 and how this would accelerate its degradation is presently unclear.
UCHL1 deubiquitinates NFKB1. 1 / 1
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It was showed that UCH-L1 over-expression inhibited NF-κB activation and decrease IL-6 and IL-8 levels, while knockdown of it enhanced NF-κB activation and increase IL-6 and IL-8 levels during TNF-α treatment.
Modified UCHL1 leads to the deubiquitination of TP53. 1 / 1
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Similarly, Li et al. have shown that over-expression of UCH-L1 in LNCaP prostate cancer cells reduces polyubiquitination of p53, leading to inhibition of degradation of p53 by the proteasome [XREF_BIBR].
UCHL1 deubiquitinates CTNNB1. 1 / 1
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Although, it is unlikely UCH-L1 directly deubiquitinates beta-catenin [XREF_BIBR, XREF_BIBR], these observations suggest UCH-L1 may convey its oncogenic function through Wnt signaling pathways.
UCHL1 deubiquitinates STUB1. 1 / 1
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No other tested DUB behaved in a similar manner : USP5 deubiquitinated Ub-CHIP in an unregulated manner, while UCHL-1 and UCHL-3 did not deubiquitinate Ub-CHIP under any conditions (XREF_FIG).
UCHL1 leads to the deubiquitination of APP. 1 / 1
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To investigate whether UCHL1 promotes the ubiquitination and degradation of APP by regulating the free ubiquitin pool, Haw cells were co-transfected with pZ-UCHL1-st and ubiquitin expression plasmid pCW7.
UCHL1 deubiquitinates SMAD3. 1 / 1
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We also found that UCH-L1 interacts, deubiquitinates, and stabilizes SMAD2 and SMAD3.
UCHL1 deubiquitinates IL6. 1 / 1
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It was showed that UCH-L1 over-expression inhibited NF-κB activation and decrease IL-6 and IL-8 levels, while knockdown of it enhanced NF-κB activation and increase IL-6 and IL-8 levels during TNF-α treatment.
UCHL1 deubiquitinates HDAC6. 1 / 1
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By reducing the production of lysine (K63)-linked ubiquitin chains, UCH-L1 inhibition decreases HDAC6 deacetylase activity and attenuates the interaction of HDAC6 and tau protein, finally leading to tau aggresome formation impairment.?
UCHL1 deubiquitinates COPS5. 1 / 1
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UCH-L1 colocalizes with Jab1 sending p27Kip1?to proteasomal degradation, prevents senescence, and ensures proper somatic cell division

Other Statements

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

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Restoring UCHL1 expression in silenced cell lines significantly inhibits their growth and colony formation ability, by inhibiting cell proliferation through cell cycle arrest in the G2/M phase and inducing apoptosis through the intrinsic caspase dependent pathway.

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UCHL1 promotes in vitro clonogenicity, cell proliferation, and invasion.

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Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Promotes Uterine Serous Cancer Cell Proliferation and Cell Cycle Progression.

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In the present study, we explored role of UCH-L1 in the regulation of TNFalpha mediated VSMC proliferation in vitro.

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Restoring UCHL1 expression in silenced cell lines significantly inhibited their growth and colony formation ability by inhibiting cell proliferation, causing cell cycle arrest in G2/M phase and inducing apoptosis through the intrinsic caspase dependent pathway.

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Thus, one could imagine further improved nerve conduits based on silk with, e.g., binding of neuron specific protein gene product 9.5 (PGP 9.5) protein onto the silk to enhance Schwann cell migration and proliferation or loading the silk with chondroitinase ABC (ChABC) or glial cell derived neurotrophic factor (GDNF) to improve axonal regeneration.

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Then, we found that knockdown of UCHL1 in osteosarcoma cell MG63 inhibited cell proliferation and significantly increased cell population in the G1 phase.

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Gain- and loss-of-function studies revealed that UCH-L1 enhances proliferation of multiple cell types, including human cancer cells.

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These data underscore the importance of the Akt pathway in malignant B-cells and provide precedence for the suggestion that UCH-L1 promotes the survival and proliferation of malignant B-cells through its effect on Akt signaling.

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Knockdown of UCHL1 in OC cell lines promoted cell proliferation and reduced cell apoptosis [XREF_BIBR] UCHL1 also promotes prostate cancer metastasis through EMT induction [XREF_BIBR].

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UCH-L1 inhibits cell proliferation in lung and neuro-blastoma cell lines; when these cell lines were treated with these inhibitors, enhanced cell proliferation was observed, further supporting the anti-proliferative role of UCLH-1 enzymes [ xref ].

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Our results uncovered for the first time that UCH-L1 facilitates autophagic degradation of p21 WAF1 and Cip1 to suppress proliferation in cardiac fibroblasts, potentially acting as a novel feedback mechanism in the regulation of maladaptive cardiac remodeling and dysfunction.

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In the present study, there are several novel findings regarding UCH-L1 as a negative regulator of maladaptive cardiac remodeling and dysfunction as follows : (i) UCH-L1 expression is enhanced in cardiac myocytes and fibroblasts during the earlier stage of cardiac adaptive hypertrophy and declined in the process of maladaptive responses to the sustained hemodynamic stress; (ii) UCH-L1 inhibits cardiac fibroblast proliferation via suppressing PDGF and PDGFRbeta signaling; (iii) UCH-L1 preferentially enhances PDGF-BB-induced suppression autophagic clearance of p21 WAF1 and Cip1 proteins in cardiac fibroblasts.

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These data suggest that UCHL1 suppresses cell proliferation of breast cancer.

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UCH-L1 siRNA is able to inhibit the proliferation of lung adenocarcinoma cell lines H157 and induce the apoptosis.

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XREF_FIG A, MTT absorbance at 490 nm of A2780-shUCHL1 and A2780-control differed significantly on the 5 th day, indicating that reduced expression of UCHL1 in A2780 cells increased cell proliferation.

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Adenoviral overexpession of UCH-L1 inhibited the PDGF induced cardiac fibroblast proliferation without affecting the activation of mitogen activated protein kinases (MAPKs), Akt, and signal transducers and activators of transcription 3 (STAT3).

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Of interest, overexpression of UCH-L1 enhanced the PDGF-BB-induced posttranscriptional upregulation of p21 WAF1 and Cip1 protein in cardiac fibroblasts (XREF_FIG), suggesting that UCH-L1 inhibits cardiac fibroblast proliferation via posttranscriptional enhancing the expression of p21 WAF1 and Cip1 to suppress the transition of G1 to S phase.

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To explore the mechanisms of how reduced expression of UCHL1 promotes cell proliferation, reduces apoptosis and confers cisplatin resistance, we performed a microarray analysis to identify different genes regulated by UCHL1-knockdown.

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Interestingly, a study found that UCH-L1 inhibits breast cancer cell proliferation by stabilizing p53 and blocking G0/G1 cell cycle [ xref ].
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Overexpression of UCHL1 has been found to induce apoptosis in MCF-7 cells XREF_BIBR.

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In summary, the present data provide evidence for the first time that UCH-L1 induces apoptosis in cultured breast cancer cells in vitro and the apoptotic effect is possibly through the PI3K and Akt pathway.

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Loss of UCHL1, a deubiquitating enzyme responsible for regenerating monoubiquitin from the ubiquitin protein complex, decreased the rate of apoptosis in the first round of spermatogenesis and increased the numbers of premeiotic germ cells in immature mice [XREF_BIBR], whereas asymmetric distribution of UCHL1 in spermatogonia is associated with maintenance and differentiation of spermatogonial stem cells [XREF_BIBR].

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Upregulation of UCHL1 enhanced the reversal effect of VER on chemo-resistance to ADM and promoted cell apoptosis.

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UCHL1 can induce apoptosis of tumor cells and is involved in various cancers XREF_BIBR - XREF_BIBR.

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These data suggest that UCHL1 inhibition suppresses MSC apoptosis induced by proinflammatory cytokines via upregulation of Bcl-2.

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Uchl1 (-/-) mice had increased ER stress and beta cell apoptosis.

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To this end, we investigated whether UCHL1 regulated proinflammatory cytokines induced MSC apoptosis.

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In mice, transgenic over-expression of UCH-L1 in spermatogonia causes a block during spermatogenesis at an early stage (pachytene) of meiosis and increased apoptosis of primary spermatocytes.

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In breast cancer, ectopic expression of UCHL1 is able to induce apoptosis by stabilizing p53.
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Knockdown of UCHL1 in OC cell lines promoted cell proliferation and reduced cell apoptosis [XREF_BIBR] UCHL1 also promotes prostate cancer metastasis through EMT induction [XREF_BIBR].

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Particularly , UCH-L1 inhibition was reported to contribute to apoptosis through the stimulation of unfolded protein response [ 218 ] .

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Since suppression UCHL1 reduced apoptosis, we performed MTT assay to determine whether UCHL1 knockdown in ovarian cancer cells influences resistance to cisplatin, a common reagent used to treat ovarian cancer.

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Results showed that UCH-L1 inhibited the growth of breast cancer cells and its action was dependent on the inducement of cell death, showing the typical characteristics of apoptosis but not necrosis.

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Moreover, inhibition of UCHL1 in MG63 cells dramatically induced cell apoptosis.

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UCH-L1 increases lymphoid proliferation and decreases apoptosis in vivo.

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Moreover, SGES upregulated the expression of GDNF, p-Akt and PGP9.5 in the vagotomized rats and inhibited the apoptosis of enteric neurons.

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Bheda et al. presented a series of genes regulated by UCH-L1 using microarray and quantitative real-time PCR analysis, and they found that the inhibition of UCH-L1 activated genes controlling apoptosi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Knockdown of UCHL1 also reduced cell apoptosis and contributed to cisplatin resistance.

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Previous studies have shown that Uch-L1 can prevent apoptosis in cells treated with lysosomal protease inhibitors.
UCHL1 affects Ubiquitin
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UCHL1 activates Ubiquitin.
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In contrast to USP14, UCH-L1 is thought to prevent the inappropriate degradation of ubiquitin by sequestering monomeric ubiquitin [XREF_BIBR].

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A neuron specific antisense lncRNA, AS Uchl1, could specifically induce the translation of ubiquitin carboxyl-terminal esterase L1 (Uchl1) under certain stress conditions through its complementarity with target mRNA [XREF_BIBR].

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AS Uchl1 enhances translation of UCHL1 (ubiquitin carboxy-terminal hydrolase L1) through an embedded SINE (short interspersed nuclear element) B2 repeat present in AS Uchl1 [XREF_BIBR].

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The increases in BAG2 (4-fold) and UCHL1 (2.7-fold) Prevent ubiquitin degradation.

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Through these functions, UCH-L1 can increase the free pool of Ub and, therefore, indirectly affect many ubiquitination dependent cellular activities.

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The I93M mutation in the UCH-L1 gene, which was reported in a German family with autosomal dominant Parkinson 's Disease (PD), leads to a 50% reduction in catalytic of UCH-L1 activity in vitro, implying that loss of UCH-L1 activity may reduce the availability of free ubiquitin, and contribute to an impaired clearance of proteins by the UPS.

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Besides TGFbeta blockade, interesting results were shown using LDN57444, a specific small molecule inhibitor, targeting ubiquitin carboxy-terminal hydrolase L1 (UCH-L1).

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Inhibition of UCHL1 using LDN-57444 depletes the hippocampus of monomeric ubiquitin and postsynaptic density protein PSD-95.

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UCHL1 associates with monoubiqutin, prolongs the half-life of ubiquitin in neurons, and resists apoptotic stress in testicular germ cells [XREF_BIBR, XREF_BIBR].

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Loss of UCHL-1 reduces free ubiquitin, and leads to inadequate ubiquitylation and protein accumulation in neurons (Osaka et al., 2003).
UCHL1 increases the amount of Ubiquitin.
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UCHL1 increases the amount of Ubiquitin. 9 / 11
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UCH-L1 may also elevate free Ub levels by facilitating recycling of Ub (XREF_FIG).

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Pharmacological suppression of UCH-L1 activity reduces monomeric ubiquitin levels and leads to dramatic alterations to synaptic structure.

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UCHL1 increases free ubiquitin levels and accelerates the lysosomal degradation of APP by promoting its ubiquitination.

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A20 overexpression or UCH-L1 inhibition increased expression of synaptoporin and nephrin but decreased desmin expression and ubiquitin accumulation level in podocytes.

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UCHL1 increases free ubiquitin level and accelerates the lysosomal degradation of APP by promoting its ubiquitination.

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In addition to the deubiquitinating or ubiquitination promoting activity, UCHL1 stabilizes monoubiquitin and increases the level of ubiquitin in neuron (Osaka et al., 2003), which is consistent with o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology.

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Pharmacological inhibition of UCH-L1 activity reduces monomeric ubiquitin levels and results in spine enlargement with a concomitant decrease in spine density and synapse number (XREF_FIG).

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UCH-L1 can increase levels of monomeric ubiquitin in neurons by binding and stabilizing ubiquitin monomers and by deubiquitinating ubiquitin precursors [XREF_BIBR, XREF_BIBR].
Modified UCHL1 increases the amount of Ubiquitin. 4 / 4
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Overexpression of UCHL1 significantly elevated free ubiquitin levels (p < 0.05) (XREF_FIG), and overexpression of ubiquitin further increased free ubiquitin levels (p < 0.01) (XREF_FIG).

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Our studies are consistent with previously published results that demonstrate that loss of Uch-L1 causes a decrease in ubiquitin levels in neurons.

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Ubiquitin C-terminal hydrolase L1 (UCHL1) plays an important role in maintenance of nervous system integrity, and overexpression of UCHL1 has been shown to increase ubiquitin levels within neurons.

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Furthermore, they also found that overexpression of wild type UCH-L1, which significantly up-regulated free monomeric ubiquitin levels, did not alter proteasome activity in vitro.
UCHL1 inhibits Ubiquitin.
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Since UCHL1 has a high affinity for ubiquitin, it has been suggested that UCHL1 may serve to sequester ubiquitin and prevent its degradation.

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In addition, western blotting of proteins from primary cells derived from the spinal ligament tissues of wild-type mice treated with the ubiquitin ligase inhibitor (HLI 373), treated with recombinant UCHL1, or transfected with miR-340 showed that expression of CXCL7 was not completely suppressed by miR-340 transfection.

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Furthermore, free monomeric ubiquitin is reduced by 20-30% in the brains of UCH-L1 deficient mice [XREF_BIBR - XREF_BIBR].
UCHL1-I93M inhibits Ubiquitin. 2 / 2
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Notably, the I93M UCHL1 mutant has markedly reduced ubiquitin hydrolase activity in vitro [XREF_BIBR], suggesting that impaired polyubiquitin hydrolysis could also contribute to dopaminergic neuronal death.

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Notably, the I93M UCHL1 mutant display markedly reduced ubiquitin hydrolase activity in vitro; suggesting that impaired polyubiquitin hydrolysis leading to a shortage of free ubiquitin might also promote the accumulation of toxic proteins and contribute to neuronal death.
UCHL1 decreases the amount of Ubiquitin.
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UCHL1 decreases the amount of Ubiquitin. 2 / 4
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Previously, we found that UCHL1 deficient testes of gad mice have reduced ubiquitin levels and are resistant to cryptorchid stress related injury.

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On the other hand, UCH-L1 deficiency does reduce ubiquitin levels in the nervous system and this is accompanied by an up-regulation of lysosomal components.
UCHL1 affects APP
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UCHL1 inhibits APP.
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UCHL1 inhibits APP. 10 / 15
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Our results indicated that UCHL1 promoted the degradation of APP via the lysosomal pathway.

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UCHL1 also accelerates beta-secretase degradation, impairs APP processing and decreases Abeta 109.

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The mechanism by which Uch-L1 reduces Abeta accumulation and toxicity is unclear.

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In APP and PS1 mice, injection of UCH-L1 improves the retention of contextual learning through the PKA-CREB pathway [XREF_BIBR] and reduces Abeta production, increased free ubiquitin and accelerates proteosomal degradation of APP [XREF_BIBR].

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In APP and PS1 mice, injection of UCH-L1 improves the retention of contextual learning through the PKA-CREB pathway [XREF_BIBR] and reduces Abeta production, increased free ubiquitin and accelerates proteosomal degradation of APP [XREF_BIBR].

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The Uchl1 overexpression, induced by intracranial injection of Uchl1 expressing virus, decreases the Abeta production and protects AD model mice against memory impairment.

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Our data also suggest that ciRS-7 modulates APP and BACE1 levels in a nuclear factor-kappaB (NF-kappaB)-dependent manner : ciRS-7 expression inhibits translation of NF-kappaB and induces its cytoplasmic localization, thus derepressing expression of UCHL1, which promotes APP and BACE1 degradation.

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Disruption of UCHL1 gene expression significantly increased APP CTFs in the hippocampi of APP23 and gad mice compared to APP23 mice (XREF_FIG).

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UCH-L1 null mice have higher levels of brain Abeta, while overexpression of UCH-L1 slows the deposition of Abeta and attenuates cognitive decline in a mouse model of AD (Zhang et al., 2012).

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Facilitation of APP degradation by UCHL1 could be through the lysosomal or proteasomal pathway.
Modified UCHL1 inhibits APP. 2 / 2
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Moreover, overexpression of UCHL1 reduces the levels of beta-secretase BACE1, and consequent BACE1 cleavage products (APP C-terminal fragment C99 and Abeta).

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Furthermore, overexpression of UCHL1 reduces the production of Abeta by downregulating the protein level of beta-secretase and APP [XREF_BIBR, XREF_BIBR].
UCHL1 decreases the amount of APP.
| 6
UCHL1 decreases the amount of APP. 4 / 7
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Mature APP level was reduced by UCHL1 as expected (p < 0.05) (XREF_FIG), and was further reduced by ubiquitin expression (p < 0.01) (XREF_FIG).

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This study suggests that potentiation of UCHL1 might be able to reduce the level of BACE1 and Abeta in brain, which makes it a novel target for AD drug development.

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Overexpressing Uch-L1 reduces BACE1 activity and Abeta levels, whereas Uch-L1 null mice exhibit increased number of Abeta plaques and neurofibrillary tangles, thus displaying an inverse relationship with Uch-L1 levels.

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To investigate whether UCHL1 reduced APP protein level by the lysosomal degradation, Haw cells were transfected with UCHL1 and then treated with 100muM chloroquine (XREF_FIG).
Modified UCHL1 decreases the amount of APP. 2 / 2
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Furthermore, viral expression of UCHL1 significantly lowered the APP level (p < 0.05) (XREF_FIG), and partial loss of UCHL1 markedly increased the APP level in APP23 and gad mice (p < 0.05) (XREF_FIG).

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Overexpression of UCHL1 significantly reduced APP CTF production (p < 0.01) (XREF_FIG) and markedly lowered Abeta level in the hippocampi of the UCHL1 overexpressing mice 10 weeks after injection (p < 0.05) (XREF_FIG).
UCHL1 activates APP.
| 1 2
UCHL1 activates APP. 3 / 6
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BACE1 has been reported to be degraded by the lysosomes and ubiquitin-proteasome pathway, and accelerating BACE1 degradation by ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) reduces 99-amino acid carboxy-terminal fragment (C99) and Abeta production.

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34 UCHL1 is also required for normal synaptic function and rescues Abeta related synaptic dysfunction in transgenic AD mice.

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UCH-L1 ameliorates Abeta ( 1-42 ) - induced LTP loss in vitro and in vivo .
UCHL1 increases the amount of APP.
| 4
Modified UCHL1 increases the amount of APP. 3 / 3
| 3

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Furthermore, viral expression of UCHL1 significantly lowered the APP level (p < 0.05) (XREF_FIG), and partial loss of UCHL1 markedly increased the APP level in APP23 and gad mice (p < 0.05) (XREF_FIG).

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UCHL1 inhibition led to marked accumulation of mature APP (p < 0.01) (XREF_FIG), whereas overexpression of UCHL1 significantly reduced mature APP level in 20E2 cells (p < 0.05) (XREF_FIG).

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Consistently, overexpression of UCHL1 increased the level of ubiquitinated wildtype APP as well (XREF_FIG).
UCHL1 increases the amount of APP. 1 / 1
| 1

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Depletion of UCHL1 increases the levels of BACE1, C99, and Abeta in the Uchl1-null gad mice.
UCHL1 affects UCHL1
| 24
UCHL1 increases the amount of UCHL1.
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UCHL1 increases the amount of UCHL1. 10 / 12
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Moreover, SMMC-7721 cells were transfected with UCHL1 overexpression vector; XREF_FIG shows transfection of UCHL1 overexpression vector effectively elevated the expression of UCHL1 in SMMC-7721 cells.

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For example, antisense Uchl1 increases UCHL1 protein levels via an embedded inverted SINEB2 element.

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AS Uchl1 caused an ~ 1.9-fold increase in UchL1 protein levels while maintaining stable Uchl1 mRNA levels, as expected for a post-transcriptional regulatory mechanism.

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PcDNA3.1-UCH-L1 plasmid and UCH-L1 siRNA caused specific and effective up- or down-regulation of UCH-L1 expression, respectively.

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25,26 The results of our current study also suggest that the expression of PGP9.5 in lung cancer may play a causative role in the oncogenic transformation of human lung epithelial cells, because 1) PG[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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AS Uchl1 induces UchL1 expression by increasing its translation.

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Our prior work revealed that UCH-L1 depletion led to cell death in three independent myeloma cell lines (KMS-11, KMS-18, KMS-28) expressing high levels of UCH-L1, whereas there was no impact on the growth of KMS-12 cells that express low levels [XREF_BIBR].

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AS Uchl1 promoted the expression of Uchl1 protein by regulating Uchl1 mRNA, while down-regulated AS Uchl1 expression induced PD disease progression.

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The Uchl1 overexpression, induced by intracranial injection of Uchl1 expressing virus, decreases the Abeta production and protects AD model mice against memory impairment.

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Given that Gene 33 deletion dramatically up-regulates UCHL1, Cr (VI) tends to promote UCHL1 expression, and that elevated UCHL1 is known to up-regulated in lung cancer, we propose that UCHL1 plays an important role in the early stage of lung epithelial cell transformation and lung tumorigenesis.
Methylated UCHL1 increases the amount of UCHL1. 1 / 1
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Promoter methylation of UCHL1 and restoration of UCHL1 expression by demethylation.
UCHL1 inhibits UCHL1.
| 3
UCHL1 inhibits UCHL1. 3 / 8
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However, there is near-complete loss of UCHL1 in the mossy fiber layer after 2h-HCA, where axon terminals from the depleted dentate granule neurons are located (XREF_FIG).

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Notably, the EMT phenotype of Cd transformed cells can be suppressed by forced ectopic expression of UCHL1, suggesting UCHL1 as a crucial modulator in the maintenance of the proper differentiation status in lung epithelial cells.

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Consistent with this view, our findings support that parkin mediated K63 linked polyubiquitination of UCH-L1 promotes the degradation of UCH-L1 by the autophagy-lysosome pathway.
UCHL1 decreases the amount of UCHL1.
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UCHL1 decreases the amount of UCHL1. 2 / 5
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XREF_BIBR Also, it has been demonstrated that ciRS-7 can repress Alzheimer 's disease (AD) development by suppressing NF-kappaB protein synthesis and inducing its cytoplasmic localization, promoting UCHL1 expression and UCHL1 induced amyloid precursor protein (APP) and BACE1 ubiquitination and degradation.

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To further confirm the role of UCH-L1 in breast cancer cell apoptosis, we used MCF7 and Adr derived cells in which over-expression of UCH-L1 was suppressed by transfection of UCH-L1 siRNA.
Methylated UCHL1 decreases the amount of UCHL1. 1 / 1
| 1

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We used HeLa cells because the expression of endogenous UCH-L1 in these cells was blocked by methylation of the UCH-L1 gene XREF_BIBR.
Modified UCHL1 decreases the amount of UCHL1. 1 / 1
| 1

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Increased striatal UCHL1 expression is also present in a mouse overexpressing wild-type SNCA and reduced UCHL1 levels reduce neuronal survival.
UCHL1 activates UCHL1.
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UCHL1 activates UCHL1. 5 / 5
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Moreover, overexpression of UCHL1 delays AD progression in mouse models, and UCHL1 gene therapy, to overexpress UCHL1, in the brain potentially could be a promising disease modifying strategy for AD therapeutics.

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This is due to very high levels of UCH-L1 which lead to an increase in the UCH-L1 substrate and also more damaged UCH-L1.

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This observation is consistent with a recent report that the over-expression of UCH-L1 induces testicular germ cell apoptosis in UCH-L1 transgenic mice.

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The loss of Cav-1 and compact myelin proteins following hyperglycemia and NRG treatment was not due to neuronal loss, since the axons remained intact and there was no loss of PGP 9.5, an axonal marker protein.

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Furthermore, there is frequent overexpression of PGP9.5 in NSCLC with higher expression correlating with advanced stage malignancy, which suggests involvement of the protein in lung carcinogenesis.
| 25

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Here we show that the remodelling process is regulated by the ubiquitin C-terminal hydrolase UCH-L1 that promotes the invasion of epithelial cells by Listeria monocytogenes and Salmonella enterica.

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UCHL1 up-regulates beta-catenin signaling and possibly promotes invasion of both Salmonella and Listeria by modulating actin dynamics in the host cell.

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Overexpression of UCHL1 in MKN45 and BGC823 cells promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity.

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Thus, these findings demonstrated that UCH-L1 promotes invasion of breast cancer cells and might serve as a potential therapeutic target for treatment of human patients with breast cancers.

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Recently, it has been suggested that UCH-L1 promotes cancer cell motility and invasion, which may contribute to its oncogenic role.

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Recently, UCH-L1 has been known to enhance tumor cell invasion and migration capability via the Akt mediated pathway [53].

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UCHL1 promotes in vitro clonogenicity, cell proliferation, and invasion.

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In non small lung cancer cell line H157, UCHL1 promotes invasion by upstream activation of Akt XREF_BIBR.

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We have further demonstrated that knockdown of UCHL1 decreased cell migration and invasion in a manner that was concomitant with less pseudopod formation in a 3D collagen matrix and significantly redu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Knocking down NOX4 in B16F10 cells significantly reduced both basal and UCH-L1 enhanced invasiveness of cells, suggesting that both inherent and UCH-L1-enhanced invasiveness of B16F10 cells depend on NOX4.

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As shown in Figure XREF_FIG, B16F10 cells overexpressing UCH-L1 showed increased ability for invasion, while knocking-down UCH-L1 decreased their invasiveness.

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Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo.

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We also found that down-regulation of UCHL1 in MG63 significantly inhibited cell invasion.

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In addition, restoration of UCHL1 inhibits tumor invasion and metastasis in vitro and in vivo.
| 1 23
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We propose that C-terminal farnesylation of UCH-L1 facilitates LMP1 loading in exosomes and might promote tumor invasion and metastasis through modulating the cancer microenvironment.

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UCH-L1 promotes cancer metastasis in prostate cancer cells through EMT induction.

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These studies suggest that UCH-L1 promotes cancer cell metastasis.

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We demonstrated that UCHL1 re-expression promoted the proliferation, migration and metastasis potential of HCT8 cells both in vitro and in vivo.

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Most of the cancer studies on UCHL1 have revealed that overexpression and promoter methylation of UCHL1 are key reasons for UCHL1 mediated metastasis.

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The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1/2 pathways.

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UCHL1 is associated with HIF-1 and distant metastasis in cancer patients, suggesting that UCHL1 may promote metastasis through HIF.

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UCHL1 has been shown to promote metastasis via the activation of HIF-1 and its overexpression also correlates with poor prognosis in patients with breast and lung cancers [XREF_BIBR].

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Together, these data imply that UCH-L1 promotes cancer cell metastasis via beta-catenin-induced EMT (XREF_FIG).

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We used an inhibitor of HIF-1, YC-1, and a plasmid expressing shRNA for HIF-1alpha, shHIF-1alpha, to directly examine the involvement of HIF-1alpha in the formation of pulmonary metastasis enhanced by UCHL1.
| 1 2

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In addition , restoration of UCHL1 inhibits tumor invasion and metastasis in vitro and in vivo .

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In addition, restoration of UCHL1 inhibits tumor invasion and metastasis in vitro and in vivo.

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They further demonstrated that depletion of UCH-L1 attenuates lung metastasis in vivo in a murine xenograft model [XREF_BIBR].
UCHL1 affects TP53
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UCHL1 activates TP53.
| 2 14
UCHL1 activates TP53. 10 / 22
| 2 14

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In breast cancer, ectopic expression of UCHL1 is able to induce apoptosis by stabilizing p53.

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The results indicated that probably the extrinsic (Fas, Fas-L, Trail, DR4 and DR5) and intrinsic (cytochrome C) apoptotic pathways, the activation of p53 (phospho-Mdm-2 and phospho-p53) and the Bcl-2 family members (pro apoptotic member Bax, anti-apoptotic members Bcl-2 and Bcl-xL) combined with each other, participating in the process of apoptosis induced by UCH-L1 in MCF7 cells.

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Interestingly, UCHL1 promotes p53 signaling in nasopharyngeal carcinoma 40 and PADI2 facilitates p53 degradation in breast cancer cells.

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It is possible that in cells with wild type p53, UCH-L1 promotes degradation p53, resulting in reduced p53 signaling and inhibition of cell death (XREF_FIG).

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Contradictorily, UCHL1 has recently been shown to induce G0/G1 cell cycle arrest and apoptosis by stabilizing p53 and has also been shown to be frequently silenced in primary breast tumors, but not in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Western blot showed that UCHL1 promoted p53 accumulation in breast tumor cells, along with the reduction of MDM2, while UCHL1 C90S did not increase p53 accumulation, but partly decreased the expression of MDM2 (XREF_FIG).

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Further studies are needed to determine specifically how UCH-L1 modulates p53.

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Furthermore, using catalytic mutant UCHL1 C90S as a control, the accumulation of p53 mediated by UCHL1 was observed, subsequently, p21, as key p53 downstream target genes and regulators of cell cycle G1/S checkpoint, as well as cleaved-caspase 3 and PARP, were obviously upregulated, accompanied by UCHL1 mediated p53 activation, but not in UCHL1 C90S expressing breast cancer cells.

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Studies showed that UCHL1 could induce apoptosis by stabilizing p53 in breast and hepatocellular carcinoma XREF_BIBR, XREF_BIBR, and promote ovarian cancer cell apoptosis associated with Bcl-2 family proteins regulated caspase activation 37.

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Western blots again indicated that UCHL1 overexpression in LNCaP cells induces accumulation of p53 whereas MDM2 protein is decreased compared to mock control cell line.
UCHL1 increases the amount of TP53.
| 4
UCHL1 increases the amount of TP53. 3 / 4
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Thus, in breast cancer models, UCHL1 can induce the levels of p53 and reduce mdm2 protein levels.

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However, the specific manner in which UCH-L1 modulates p53 level and function remains controversial.

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On the contrary, UCH-L1 elevates p53 levels in MDA-MB-231 and HONE1 cells, which express DNA binding domain mutant p53 with little to no transcriptional activity [XREF_BIBR - XREF_BIBR] and LNCaP cells, which have also been reported to express DNA binding domain mutant p53 [XREF_BIBR], although this is controversial [XREF_BIBR].
Modified UCHL1 increases the amount of TP53. 1 / 1
| 1

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On the other hand, overexpression of UCH-L1 was reported to increase p53 levels in MDA-MB-231 breast carcinoma cells [XREF_BIBR] and HONE1 nasopharyngeal carcinoma cells [XREF_BIBR].
UCHL1 inhibits TP53.
| 2
UCHL1 inhibits TP53. 2 / 2
| 2

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Interestingly, UCHL1 promotes p53 signaling in nasopharyngeal carcinoma 40 and PADI2 facilitates p53 degradation in breast cancer cells.

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It is also possible that UCH-L1 indirectly elicits control over p53 by modulating negative regulators of p53, such as mdm2, as suggested by Li et al. [XREF_BIBR].
| 23
| 21

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Mutations in the gene encoding alpha-synuclein represent autosomal dominant familial PD, and mutations in genes encoding parkin, UCHL1, DJ-1, PINK1, and LRRK2 cause autosomal recessive familial PD.

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SNCA, UCH-L1, and LRRK2 mutations cause autosomal dominant PD and the remaining gene mutations autosomal recessive PD.

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For example, in addition to the forms of PD caused by UCH-L1 and parkin mutations (Leroy et al., 1998; Kitada et al., 1998; Shimura et al., 2000), a mutant form of Ub called Ub +1 has been detected in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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AS Uchl1 promoted the expression of Uchl1 protein by regulating Uchl1 mRNA, while down-regulated AS Uchl1 expression induced PD disease progression.

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A missense mutation in the UCH-L1 gene (PARK5), resulting in the amino acid substitution Ile 93 --> Met, can also cause very rare autosomal dominant PD [XREF_BIBR].

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The genes SNCA (PARK1), UCHL1 (PARK5), LRRK2 (PARK8), GIGYF2 (PARK11), OMI and HTRA2 (PARK13), VPS35 (PARK17), and EIF4G1 (PARK18) result in autosomal dominant PD, and PRKN (PARK2), DJ-1 (PARK7), ATP13A2 (PARK9), PLA2G6 (PARK14), FBX07 (PARK15), DNJC6 (PARK19), and SYNJ1 (PARK20) causes autosomal recessive PD.

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Mutations in alpha-synuclein and UchL1 cause autosomal dominant PD and mutations in parkin and DJ-1 cause autosomal recessive PD.

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Mutations in alpha-synuclein XREF_BIBR, parkin XREF_BIBR, DJ-1 XREF_BIBR, PINK-1 XREF_BIBR, UCH-L1 XREF_BIBR, LRRK2 XREF_BIBR, ATP13A2 XREF_BIBR, Omi and HtrA2 XREF_BIBR and NR4A2 XREF_BIBR have been reported to cause familial PD.

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No pathological data are currently available.It is not clear why mutations in alpha-synuclein, parkin or UCH-L1 genes cause nigral dopaminergic cell death in familial PD.

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In PD, one study presents evidence for mutations in UCH-L1 causing familial PD [XREF_BIBR].
Mutated UCHL1 activates Parkinson Disease. 2 / 2
| 2

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Our findings may provide novel insights into the molecular links between alpha-synuclein and UCH-L1 and suggest that aberrant interaction of mutant UCH-L1 with CMA machinery, at least partly, underlies the pathogenesis of PD associated with I93M UCH-L1.

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Also, a mutant of UCH-L1, I93M (Ile93 to Met), was shown to cause a type of autosomal dominant PD in one German family XREF_BIBR.
| 2

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Accordingly, a mutant form of UCH-L1 with decreased E3 ligase activity upon dimerization, but normal DUB activity, decreases PD pathogenesis.

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In conclusion, this study in a Swedish case-control sample demonstrates that the S18Y variant in UCH-L1 decreases risk of PD and in particular PD with age of onset below 50 years of age and further st[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
UCHL1 affects HIF1
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UCHL1 activates HIF1.
| 1 18
UCHL1 activates HIF1. 10 / 18
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Because HIF-1 activity is known to be regulated at multiple steps, we first aimed to identify the key regulatory mechanism in the UCHL1 mediated activation of HIF-1 in EMT6 cells.

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First, we performed a luciferase assay using the 5HRE-luc reporter gene 43, which expresses luciferase bioluminescence in a HIF-1-dependent manner, in order to test whether UCHL1 enhanced HIF-1 activity in EMT6 cells.

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The inhibitor of UCHL1, LDN-57444 (XREF_FIG J), blocks the UCHL1-HIF1 axis and therefore inhibits HIF-1 activity as UCHL1 deubiquitinate and stabilizes HIF-1alpha.

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These results suggested that the expression of UCHL1 would lead to a poor prognosis by activating HIF-1; therefore, it could be a useful prognostic marker.

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We then examined the molecular mechanisms underlying the upregulation of HIF-1 by UCHL1.

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The inhibitor of UCHL1 , LDN-57444 ( Figure 6J ) , blocks the UCHL1-HIF1 axis and therefore inhibits HIF-1 activity as UCHL1 deubiquitinate and stabilizes HIF-1alpha .

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In order to fully elucidate the molecular mechanisms underlying the UCHL1 mediated upregulation of HIF-1 activity, further investigation is needed.

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We performed a luciferase assay using the 5HREp-luc reporter gene, which expressed firefly luciferase under the control of 5HREp XREF_BIBR XREF_BIBR, to examine whether UCHL1 induced HIF-1 activity.

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These results collectively indicate that UCHL1 stabilizes HIF-1alpha protein, and elicits HIF-1 activity in a deubiquitinating activity dependent manner in EMT6 cells.

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In the present study, we provided direct evidence to show that UCHL1 was responsible for the deubiquitination of HIF-1alpha and upregulated HIF-1 activity.
UCHL1 bound to HIF1A activates HIF1. 1 / 1
| 1

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We revealed that UCHL1 directly interacts with HIF-1alpha, mediates the deubiquitination of HIF-1alpha, and upregulates HIF-1 activity through the stabilization of HIF-1alpha.
UCHL1-C90S activates HIF1. 1 / 1
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The luciferase assay using the 5HRE-luc reporter gene showed that a catalytically inactive mutant of UCHL1, UCHL1 C90S 46, failed to upregulate HIF-1 activity.
Mutated UCHL1 activates HIF1. 1 / 1
| 1

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The luciferase assay using the 5HRE-luc reporter gene showed that a catalytically inactive mutant of UCHL1, UCHL1 C90S 46, failed to upregulate HIF-1 activity.
UCHL1 increases the amount of HIF1.
| 2
Modified UCHL1 increases the amount of HIF1. 1 / 1
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The resultant clones, EMT6/EF-Luc/UCHL1 and EMT6/EF-Luc/EV cells, showed that the forced expression of UCHL1 induced the expression of HIF-1alpha and HIF-1 activity (XREF_SUPPLEMENTARY) and enhanced cell migration (XREF_SUPPLEMENTARY), but did not promote cell proliferation in vitro, EF-Luc reporter activity or the growth of tumour xenografts following subcutaneous transplantation (XREF_SUPPLEMENTARY).
UCHL1 increases the amount of HIF1. 1 / 1
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Finally, inhibition of UCHL1 promoted HIF-1alpha degradation and lowered the expression of HIF-1 target genes in the 3D model, as also observed in 2D monolayer culture.
| 1 1 17
UCHL1 activates cell migration.
| 1 13
| 1 12

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We found that UCH-L1 expression increases apoptotic resistance in the adenocarcinoma cell line (H838) and promotes cell migration in the H157 squamous cell carcinoma cell line.

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UCH-L1 promotes cell migration in H157 cells.

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Moreover , in vitro tumorigenesis studies showed that UCHL1 expression stimulated oncogenesis and an invasive phenotype 117-119 , whereas UCHL1 depletion had antitumour effects and blocked cell migration in a lung cancer cell line 117 .

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In our previous report, we demonstrated that UCH-L1 promotes prostate cancer cell migration and invasion through EMT induction [11].

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This is consistent with our previous finding in H157 cells that UCH-L1 increases cell migration by modulating Akt activation [XREF_BIBR].

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Overexpression of UCH-L1 remodeled its actin cytoskeleton, increased its cell migration and impacted its important proteins.

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Moreover, in vitro tumorigenesis studies showed that UCHL1 expression stimulated oncogenesis and an invasive phenotype 117-119 , whereas UCHL1 depletion had antitumour effects and blocked cell migration in a lung cancer cell line 117 .

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In the Transwell and wound healing assays, we found that knockdown of UCHL1 significantly reduced cell migration, motility, and invasiveness.

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UCH-L1 stimulates prostate cancer cell migration and invasion as well by promoting epithelial-to-mesenchymal transition (EMT) [XREF_BIBR].

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We have further demonstrated that knockdown of UCHL1 decreased cell migration and invasion in a manner that was concomitant with less pseudopod formation in a 3D collagen matrix and significantly redu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Modified UCHL1 activates cell migration. 1 / 1
| 1

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The resultant clones, EMT6/EF-Luc/UCHL1 and EMT6/EF-Luc/EV cells, showed that the forced expression of UCHL1 induced the expression of HIF-1alpha and HIF-1 activity (XREF_SUPPLEMENTARY) and enhanced cell migration (XREF_SUPPLEMENTARY), but did not promote cell proliferation in vitro, EF-Luc reporter activity or the growth of tumour xenografts following subcutaneous transplantation (XREF_SUPPLEMENTARY).
UCHL1 inhibits cell migration.
| 1 4
| 1 3

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Results showed that high level UCHL1-AS1 could effectively inhibit HCC cell migration.

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Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo.

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HIF-1alpha silencing was confirmed to suppress the UCHL1 mediated promotion of cell migration in a Transwell migration assay (XREF_FIG).

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Silencing UCH-L1, as well as inhibition of H 2 O 2 generation by catalase or by DPI, a NOX inhibitor, suppressed the migration potential of B16F10 cells, indicating that UCH-L1 promotes cell migration by up-regulating H 2 O 2 generation.
Modified UCHL1 inhibits cell migration. 1 / 1
| 1

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In this present study it was shown that reduced expression of UCH-L1 in H157 cells led to decreased phosphorylation of MLC2, suggesting that UCH-L1 may be involved in tumour cell migration.
UCHL1 affects AKT
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UCHL1 activates AKT.
| 1 9
UCHL1 activates AKT. 9 / 12
| 1 8

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While UCH-L1 has been shown to inhibit alpha 2 -adrenergic receptor (AR) agonist mediated activation of ERK via a direct association with alpha 2A -AR receptor implicating a role of UCH-L1 in neuro-protection XREF_BIBR, it has also been documented that UCH-L1 up-regulates oncogenic beta-catenin and TCF and Akt signaling to induce tumor cell proliferation and migration contributing to tumor progression XREF_BIBR, XREF_BIBR.

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Nevertheless, stimulation of Akt by UCH-L1 and the subsequent promotion of prosurvival signaling may contribute to the function of UCH-L1 in oncogenesis.

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UCHL1 activated Akt and Erk1/2, which process also required enzymatic activity and was necessary for mediating cell migration and invasion.

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UCHL1 activated Akt and Erk1/2, which process also required enzymatic activity and was necessary for mediating cell migration and invasion.

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Finally, we demonstrated that overexpression of UCH-L1 led to activation of Akt as evidenced by upregulation of phosphorylated Akt.

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Additionally, it might be possible that activation of Akt signaling by UCH-L1 [XREF_BIBR, XREF_BIBR] might also contribute to its control over p53, as Akt is an established negative regulator of p53 activity [XREF_BIBR, XREF_BIBR].

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These findings demonstrated that UCHL1 promoted cell proliferation, migration, and invasion depending on its de-ubiquitinase activity by activating Akt and Erk1/2, which may account for its higher positive expression rate in liver metastases from gastric cancer.

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Together, these data suggest UCH-L1 elicits at least some of its cellular effects through Akt dependent signaling and that stimulation of Akt by UCH-L1 is a potential mechanism of UCH-L1-mediated oncogenesis (XREF_FIG).

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Similarly, the deubiquitinating enzyme UCHL1 has been shown to enhance AKT pathway activation by suppressing the levels of PHLPP1 an effect found to drive the development of lymphoma in vivo [206].
Modified UCHL1 activates AKT. 1 / 1
| 1

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As expected, overexpression of UCHL1 significantly enhanced cardiomyocyte size, the mRNA level of ANF, and the protein levels of EGFR, and phosphorylated EGFR, AKT, and EKR1/2 compared with coinfection with Ad-GFP and siRNA-control after PE stimulation; moreover, this effect was markedly attenuated by coinfection with Ad-GFP or Ad-UCHL1 and siRNA-EGFR.
UCHL1 inhibits AKT.
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UCHL1 inhibits AKT. 4 / 5
| 4

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These data provide the first in vivo evidence for DUB driven oncogenesis and suggest that UCH-L1 hyperactivity deregulates normal Akt signaling.

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Our data suggest that PI3K and Akt pathway is possibly involved in apoptosis in breast cancer cells and blocked by UCH-L1.

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Taken together, it appears that UCHL1 suppresses the growth of LNCaP cells via stabilization of tumour suppressor protein such as p53 and by inactivating AKT and PKB pathway.

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Taken together, it appears that UCHL1 suppresses the growth of LNCaP cells via stabilization of tumour suppressor protein such as p53 and by inactivating AKT and PKB pathway.
UCHL1 increases the amount of AKT.
| 1
UCHL1 increases the amount of AKT. 1 / 1
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We also observed that silencing of UCH-L1 decreased the phosphorylation level of Akt and PCNA in the xenograft experiments.
UCHL1 decreases the amount of AKT.
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UCHL1 decreases the amount of AKT. 1 / 1
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Knockdown of UCHL1 markedly reduced the protein levels of total EGFR and phosphorylated EGFR, AKT, and ERK1/2, with no effect on the EGFR mRNA level compared with the siRNA-controls after saline or PE stimulation.
UCHL1 affects translation
| 1 17
UCHL1 activates translation.
| 1 16
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Antisense Uchl1 RNA promotes association of Uchl1 mRNA with active polysomes and enhances protein translation.

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The mature lncRNA contains a 73-nucleotide complementary site with the 5 ' end of the Uchl1 mRNA, which serves to upregulate translation of Uchl1 mRNA [XREF_BIBR].

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Antisense Uchl1 specifically promotes the translation of UCHL1 under rapamycin treatment.

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In addition, another lncRNA antisense Uchl1, which activates uchl1 translation through the embedded SINEB2 repeat, also enhances the association of Uchl1 mRNA to active polysomes XREF_BIBR.

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Exact molecular mechanism as to how AS Uchl1 promotes the translation of Uchl1 mRNA under stress conditions is still elusive.

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A neuron specific antisense lncRNA, AS Uchl1, could specifically induce the translation of ubiquitin carboxyl-terminal esterase L1 (Uchl1) under certain stress conditions through its complementarity with target mRNA [XREF_BIBR].

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In a similar case, this new mechanism was also proposed by one previous work which reported that the uchl1 gene lncRNA enhances the translation of its target mRNA via base pairing and by recruiting additional ribosomes via the functional element.

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In addition, another lncRNA antisense Uchl1, which activates uchl1 translation through the embedded SINEB2 repeat, also enhances the association of Uchl1 mRNA to active polysomes xref .

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TINCR is induced during epidermal differentiation and is required for stability of differentiation mediators and antisense Uchl1 lncRNA promotes translation of Uchl1 in mouse.

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Under stress conditions where cap dependent translation is inhibited, antisense Uchl1 IncRNA, previously enriched in the nucleus, moves into the cytoplasm and hybridizes with Uchl1 mRNA to enable cap independent translation of Uchl1.
UCHL1 inhibits translation.
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Under cap dependent translation inhibition due to stress, UCHL1 lncRNA moves from the nucleus to the cytoplasm, binds to Uchl1 mRNA and allows its cap independent translation.
UCHL1 affects cell cycle
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UCHL1 inhibits cell cycle.
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Furthermore, cell cycle analysis revealed up-regulation of S phase both in A2780-shUCHL1 and IGROV1-shUCHL1, indicating that UCHL1 knockdown promoted cell proliferation by progressing cell cycle.

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Other recent studies have found that UCHL1 could promote tumor cell proliferation and inhibit cell cycle arrest XREF_BIBR, which are involved in the development of chemoresistance in cervical cancer and pancreatic cancer XREF_BIBR, XREF_BIBR.

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Restoring UCHL1 expression in silenced cell lines significantly inhibited their growth and colony formation ability by inhibiting cell proliferation, causing cell cycle arrest in G2/M phase and inducing apoptosis through the intrinsic caspase dependent pathway.

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Suppression of UCHL1 protein level by LDN-5744 inhibitor could arrest the cell cycle in G1 phase in cell lines.

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Targeting UCHL1 Induces Cell Cycle Arrest in High-Risk Multiple Myeloma with t (4; 14).

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Our data showed a low expression of Uch-L1 in UT-B null bladder epithelium and supports that inhibition of Uch-L1 induced cell cycle arrest and apoptosis XREF_BIBR, XREF_BIBR, XREF_BIBR.

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Bheda et al. presented a series of genes regulated by UCH-L1 using microarray and quantitative real-time PCR analysis, and they found that the inhibition of UCH-L1 activated genes controlling apoptosi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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We showed that knockdown of UCHL1 in ovarian cancer cells promoted cell proliferation by inducing S phase cell cycle and reduced apoptosis.
UCHL1 activates cell cycle.
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Contradictorily, UCHL1 has recently been shown to induce G0/G1 cell cycle arrest and apoptosis by stabilizing p53 and has also been shown to be frequently silenced in primary breast tumors, but not in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UCHL1 has been observed to be epigenetically regulated in other cancers, and is believed to induce G0/G1 cell cycle arrest and apoptosis by stabilization of p53.

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Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Promotes Uterine Serous Cancer Cell Proliferation and Cell Cycle Progression.

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UCHL1 promoted cell cycle progression and DNA repair through regulating TS.

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Suppression of UCHL1 protein level by LDN-5744 inhibitor could arrest the cell cycle in G1 phase in cell lines.

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UCH-L1 has been shown to modulate the levels of several cell cycle regulators in cancer cells including cyclin D [XREF_BIBR] and p53 [XREF_BIBR].

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The related mechanisms for this resistance appear to involve UCHL1 promoting cell cycle progression and DNA repair.

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The Ubiquitin Peptidase UCHL1 Induces G0/G1 Cell Cycle Arrest and Apoptosis Through Stabilizing p53 and Is Frequently Silenced in Breast Cancer.
UCHL1 affects SNCA
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UCHL1 inhibits SNCA.
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UCHL1 inhibits SNCA. 6 / 6
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As an example, inhibition of UCHL-1 in rat ventral mesencephalic neurons induces intracellular alpha-synuclein aggregates (McNaught et al., 2002a).

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In addition, UCH-L1 inhibition by LDN-57444 treatment also enhanced cell-to-cell transmission of alpha-synuclein (XREF_FIG).

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Severing UCHL1 from the membrane might increase the degradation of alpha-synuclein, effectively reducing levels of this aggregation-prone protein and alleviating neuronal stress.

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Membrane associated UCH-L1 has been reported to promote alpha-syn neurotoxicity by possibly negatively regulating the lysosomal degradation of alpha-syn.

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Severing UCHL1 from the membrane might increase degradation of alpha-synuclein, effectively reducing levels of this aggregation-prone protein and alleviating neuronal stress.

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The mechanism of icariin may be related to upregulate Parkin and UCH-L1 expression in ubiquitin-proteasome system and HSP70 in molecular chaperone, thus enhancing the degradation of alpha-synuclein.
UCHL1 activates SNCA.
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UCHL1 activates SNCA. 5 / 5
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The UCH-L1 ligase activity could produce an elevation of the cytoplasmic concentration of alpha-synuclein by inhibiting its " normal " degradation.

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Fractions containing both UCH-L1 and alpha-synuclein were treated with a UCH-L1 antibody (Chemicon, rabbit polyclonal), an alpha-synuclein antibody (Transduction Lab), or buffer (as a control), and th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UCH-L1, especially those variants linked to higher susceptibility to PD, causes the accumulation of alpha-synuclein in cultured cells, an effect that can not be explained by its recognized hydrolase activity.

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This result indicates that UCH-L1 transfection does not increase alpha-synuclein expression and that accumulation of alpha-synuclein resulted from inhibition of its degradation.

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This further sustains the notion that UCH-L1 plays a pathological role in inclusion formation, e.g., in PD, and may modulate the turnover of alpha-syn.
UCHL1 increases the amount of SNCA.
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UCHL1 increases the amount of SNCA. 3 / 3
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Reduction of UCH-L1 (M) in cell culture models of alpha-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces alpha-synuclein levels and increases cell viability.

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Chemical inhibition of UCHL1 by farnesylation may reduce alpha-synuclein levels and improve neuronal cell viability in cellular models of alpha-synuclein-associated toxicity for PD.

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In this line, in vitro studies using a crude cell-free system where alpha-synuclein was conjugated to histidine tagged ubiquitin revealed that the addition of UCHL-3 had little effect, whereas the add[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Farnesylated UCHL1 increases the amount of SNCA. 1 / 1
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Chemical inhibition of UCHL1 farnesylation reduces the cellular level of alpha-synuclein and thus improves neuronal cell viability.
UCHL1 decreases the amount of SNCA.
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UCHL1 decreases the amount of SNCA. 1 / 1
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Since UCHL1 inhibition increases cytoplasmic alpha-synuclein levels, UCHL1 mutation might interfere with vesicular catecholamine storage in a manner similar to that in PARK1 and PARK4.
UCHL1 affects CDKN1A
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UCHL1 activates CDKN1A.
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UCHL1 activates CDKN1A. 8 / 8
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In the present study, there are several novel findings regarding UCH-L1 as a negative regulator of maladaptive cardiac remodeling and dysfunction as follows : (i) UCH-L1 expression is enhanced in cardiac myocytes and fibroblasts during the earlier stage of cardiac adaptive hypertrophy and declined in the process of maladaptive responses to the sustained hemodynamic stress; (ii) UCH-L1 inhibits cardiac fibroblast proliferation via suppressing PDGF and PDGFRbeta signaling; (iii) UCH-L1 preferentially enhances PDGF-BB-induced suppression autophagic clearance of p21 WAF1 and Cip1 proteins in cardiac fibroblasts.

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In the present study, there are several novel findings regarding UCH-L1 as a negative regulator of maladaptive cardiac remodeling and dysfunction as follows : (i) UCH-L1 expression is enhanced in cardiac myocytes and fibroblasts during the earlier stage of cardiac adaptive hypertrophy and declined in the process of maladaptive responses to the sustained hemodynamic stress; (ii) UCH-L1 inhibits cardiac fibroblast proliferation via suppressing PDGF and PDGFRbeta signaling; (iii) UCH-L1 preferentially enhances PDGF-BB-induced suppression autophagic clearance of p21 WAF1 and Cip1 proteins in cardiac fibroblasts.

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Of interest, overexpression of UCH-L1 enhanced the PDGF-BB-induced posttranscriptional upregulation of p21 WAF1 and Cip1 protein in cardiac fibroblasts (XREF_FIG), suggesting that UCH-L1 inhibits cardiac fibroblast proliferation via posttranscriptional enhancing the expression of p21 WAF1 and Cip1 to suppress the transition of G1 to S phase.

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UCH-L1 enhances PDGF-BB-induced upregulation of p21 WAF1 and Cip1 proteins via suppressing autophagic clearance of p21 WAF1 and Cip1 independent of ubiquitin-proteasomal system (UPS)-mediated protein degradation.

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UCH-L1 enhances PDGF-BB-induced upregulation of p21 WAF1 and Cip1 proteins via suppressing autophagic clearance of p21 WAF1 and Cip1 independent of ubiquitin-proteasomal system (UPS)-mediated protein degradation.

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To explore the underlying mechanism by which UCH-L1 enhances PDGF-BB-induced posttranscriptional upregulation of p21 WAF1 and Cip1, we determined a potential role of UCH-L1 in regulating p21 clearance by UPS and autophagy, two major pathways in the posttranscriptional control of protein levels XREF_BIBR.

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Of interest, overexpression of UCH-L1 enhanced the PDGF-BB-induced posttranscriptional upregulation of p21 WAF1 and Cip1 protein in cardiac fibroblasts (XREF_FIG), suggesting that UCH-L1 inhibits cardiac fibroblast proliferation via posttranscriptional enhancing the expression of p21 WAF1 and Cip1 to suppress the transition of G1 to S phase.

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To explore the underlying mechanism by which UCH-L1 enhances PDGF-BB-induced posttranscriptional upregulation of p21 WAF1 and Cip1, we determined a potential role of UCH-L1 in regulating p21 clearance by UPS and autophagy, two major pathways in the posttranscriptional control of protein levels XREF_BIBR.
UCHL1 increases the amount of CDKN1A.
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UCHL1 increases the amount of CDKN1A. 4 / 4
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We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S expressed cells.

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However, in the presence of MG132, PDGF-BB was still able to upregulate p21 WAF1 and Cip1 protein levels while overexpression of UCH-L1 enhanced not only the PDGF-BB-induced upregulation of p21 WAF1 and Cip1 protein in presence of MG132 but also the basal increased p21 WAF1 and Cip1 protein level induced by MG132 per se (XREF_FIG, XREF_SUPPLEMENTARY).

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Taken together, these findings demonstrate that UCH-L1 potentiates PDGF-BB-induced upregulation of p21 WAF1 and Cip1 protein expression via suppressing autophagic protein clearance in cardiac fibroblasts.

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These results suggest that UCH-L1 enhance PDGF-BB-induced p21 WAF1 and Cip1 protein expression via suppressing autophagy activation by increasing mTOR activity.
Modified UCHL1 increases the amount of CDKN1A. 1 / 1
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Overexpression of UCH-L1 enhanced PDGF-BB-induced mTOR phosphorylation and upregulation of p21 WAF1 and Cip1 protein expression while suppressed autophagic flux in cardiac fibroblasts.
UCHL1 decreases the amount of CDKN1A.
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UCHL1 decreases the amount of CDKN1A. 2 / 2
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In contrast, UCHL1 silencing or inhibition in PEM-R cells decreased the levels of c-Myc and Cyclin D1 and increased the levels of p21 (a cell cycle arrest related protein).

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We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S expressed cells.
UCHL1 inhibits CDKN1A.
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UCHL1 inhibits CDKN1A. 1 / 1
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Thus, whether UCH-L1 regulates these molecular events to suppress autophagic clearance of p21 WAF1 and Cip1 proteins deserves further investigation in cardiac fibroblasts.
UCHL1 affects CTNNB1
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UCHL1 activates CTNNB1. 6 / 14
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These observations imply that UCHL1 may contribute to CRC progression by activating the beta-catenin and TCF pathway through its deubi quitinating activity.

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UCHL1 up-regulates beta-catenin signaling and possibly promotes invasion of both Salmonella and Listeria by modulating actin dynamics in the host cell.

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Aberrant expression of UCHL1 in pediatric high-grade gliomas may promote cell invasion, transformation, and self-renewal properties, at least in part, by modulating Wnt and Beta catenin activity.

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In contrast, other studies have documented that UCH-L1 up-regulates beta-catenin and TCF via a positive feedback mechanism or exerts anti-apoptotic and growth stimulating effects, supporting an oncogenic potential of UCH-L1 [XREF_BIBR, XREF_BIBR].

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Of note, UCHL1 also promotes the activity of the WNT pathway by stabilizing beta-catenin.

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While UCH-L1 has been shown to inhibit alpha 2 -adrenergic receptor (AR) agonist mediated activation of ERK via a direct association with alpha 2A -AR receptor implicating a role of UCH-L1 in neuro-protection XREF_BIBR, it has also been documented that UCH-L1 up-regulates oncogenic beta-catenin and TCF and Akt signaling to induce tumor cell proliferation and migration contributing to tumor progression XREF_BIBR, XREF_BIBR.
UCHL1 affects NOX4
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UCHL1 activates NOX4.
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UCHL1 activates NOX4. 7 / 13
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These results suggest that UCH-L1 restores H 2 O 2 -generating activity of NOX4 through deubiquitination.

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To verify whether UCH-L1 is involved in NOX4-mediated HO generation in HUVEC, we examined NOX4 activation by UCH-L1.

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Because silencing UCH-L1 inhibited the phosphorylation of VEGFR, a signal for angiogenesis, this finding provides another evidence that UCH-L1 promotes ROS generation in HUVECs, and plays a key role i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UCH-L1 induced active NOX4 by deubiquitination of NOX4, and then increased ROS which induce angiogenesis in HUVECs.

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The present study clearly shows that UCH-L1 increases H 2 O 2 level in HUVECs as well as in melanoma cells by activating NOX4 via deubiquitination [13].

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In summary, we demonstrated that UCH-L1 promotes H 2 O 2 generation by up-regulating NOX4 activity through deubiquitination, and that H 2 O 2, so produced, plays an important role in cell invasion in vitro by regulating the upstream kinase Akt.

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Here we demonstrated that UCH-L1-dependent NOX4 is involved in VEGF mediated endothelial responses through VEGFR2, suggesting that UCH-L1 may be a novel potential therapeutic target in the treatment o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
UCHL1 inhibits NOX4.
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UCHL1 inhibits ubiquitinated NOX4. 1 / 1
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UCH-L1 decreases ubiquitinated NOX4.
UCHL1 affects BACE1
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UCHL1 inhibits BACE1.
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UCHL1 inhibits BACE1. 5 / 5
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Our data also suggest that ciRS-7 modulates APP and BACE1 levels in a nuclear factor-kappaB (NF-kappaB)-dependent manner : ciRS-7 expression inhibits translation of NF-kappaB and induces its cytoplasmic localization, thus derepressing expression of UCHL1, which promotes APP and BACE1 degradation.

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Specifically, UCH-L1 appears to increase lysosomal degradation of BACE1, as inhibition of UCH-L1 caused a significant increase in BACE1 protein levels in several cell types, and loss of UCH-L1 gene function in gad mice significantly increased levels of endogenous BACE1, C99, and Abeta peptides [XREF_BIBR, XREF_BIBR].

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In this study we demonstrated that Uch-L1 inhibition induces BACE1 up-regulation and increases neuronal and apoptotic cell death in control as well as in transgenic AD mouse model subjected to Bengal Rose, a light sensitive dye inducing that induces a cortical infarction through photo activation.

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In this study we demonstrated that the inhibition of Uch-L1 induces BACE1 up-regulation and increases neuronal cell death in control as well as in AD transgenic mouse models subjected to Bengal Rose, a light sensitive dye inducing a cortical infarction through photo activation.

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These results demonstrated that UCHL1 accelerates BACE1 degradation and affects APP processing and Abeta production.
Modified UCHL1 inhibits BACE1. 1 / 1
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Moreover, overexpression of UCHL1 reduces the levels of beta-secretase BACE1, and consequent BACE1 cleavage products (APP C-terminal fragment C99 and Abeta).
UCHL1 decreases the amount of BACE1.
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UCHL1 decreases the amount of BACE1. 4 / 5
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This study suggests that potentiation of UCHL1 might be able to reduce the level of BACE1 and Abeta in brain, which makes it a novel target for AD drug development.

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The restoration of Uch-L1 was able to completely prevent the increase of BACE1 protein levels both in control and Tg mice at 6 h post injury, as reported by the representative blot and by the densitometric analysis.

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Thus, the restoration of Uch-L1 was able to completely prevent both the increase in BACE1 protein levels and the amount of cell death.

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We found that inhibition of UCHL1 significantly increased BACE1 protein level in a time dependent manner.
Modified UCHL1 decreases the amount of BACE1. 1 / 1
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Moreover, overexpression of UCHL1 reduces the levels of beta-secretase BACE1, and consequent BACE1 cleavage products (APP C-terminal fragment C99 and Abeta).
UCHL1 increases the amount of BACE1.
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