COPS5 Data Analysis

HGNC Gene Name
COP9 signalosome subunit 5
HGNC Gene Symbol
COPS5
Identifiers
hgnc:2240 NCBIGene:10987 uniprot:Q92905
Orthologs
mgi:1349415 rgd:1310301
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for COPS5
Number of Papers
357 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
COPS4 COP9 signalosome subunit 4 0.315 BioGRID IntAct INDRA (15) Reactome (13) 0.83 4.50 2.50e-94
COPS3 COP9 signalosome subunit 3 0.301 BioGRID IntAct INDRA (9) Reactome (13) 0.80 4.29 8.82e-80
COPS8 COP9 signalosome subunit 8 0.3 BioGRID IntAct INDRA (13) Reactome (13) 0.30 1.54 5.77e-08
COPS6 COP9 signalosome subunit 6 0.271 BioGRID IntAct INDRA (17) Reactome (13) 0.78 4.20 2.40e-74
CAND1 cullin associated and neddylation dissociated 1 0.26 BioGRID INDRA (2) Reactome (3) 0.45 2.41 1.24e-18
GPS1 G protein pathway suppressor 1 0.254 BioGRID IntAct INDRA (12) Reactome (13) 0.71 3.81 6.06e-55
COPS2 COP9 signalosome subunit 2 0.242 BioGRID IntAct INDRA (11) Reactome (13) 0.75 4.05 3.10e-66

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with COPS5using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value
GO:0000338 protein deneddylation Biological Process 2.27e-20 1.63e-18 8.12e-19
GO:0000715 nucleotide-excision repair, DNA damage recognition Biological Process 1.09e-17 7.85e-16 1.95e-16
GO:0008180 COP9 signalosome Cellular Component 2.10e-16 1.51e-14 2.51e-15
GO:0006283 transcription-coupled nucleotide-excision repair Biological Process 1.83e-14 1.32e-12 1.64e-13
GO:0006289 nucleotide-excision repair Biological Process 2.18e-13 1.57e-11 1.56e-12
GO:0043687 post-translational protein modification Biological Process 8.86e-13 6.38e-11 5.28e-12
GO:0070646 protein modification by small protein removal Biological Process 1.01e-10 7.25e-09 5.15e-10

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out COPS5 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
G0S2 G0/G1 switch 2 8.51e-01 3.08e-30 6.04e-27
MMP1 matrix metallopeptidase 1 5.54e-01 1.61e-14 1.58e-11
SERPINE1 serpin family E member 1 6.72e-01 1.51e-11 9.83e-09
ANKRD1 ankyrin repeat domain 1 5.26e-01 3.97e-11 1.95e-08
FRMD6 FERM domain containing 6 6.68e-01 1.60e-10 6.27e-08
SLCO4A1 solute carrier organic anion transporter family member 4A1 -7.51e-01 7.03e-10 2.30e-07
CXCL8 C-X-C motif chemokine ligand 8 9.63e-01 3.30e-08 9.25e-06
HMGB3 high mobility group box 3 -4.18e-01 1.28e-06 3.14e-04
PLAUR plasminogen activator, urokinase receptor 3.84e-01 3.17e-06 6.91e-04
CXCL1 C-X-C motif chemokine ligand 1 8.17e-01 4.00e-06 7.84e-04
CSF2 colony stimulating factor 2 6.80e-01 4.51e-06 8.03e-04
NQO1 NAD(P)H quinone dehydrogenase 1 -4.03e-01 6.59e-06 1.08e-03
ALDOA aldolase, fructose-bisphosphate A -2.85e-01 9.84e-06 1.48e-03
NOP16 NOP16 nucleolar protein 3.96e-01 1.79e-05 2.50e-03
PTX3 pentraxin 3 5.18e-01 3.52e-05 4.60e-03
CCNB1 cyclin B1 -3.25e-01 5.54e-05 6.79e-03
YY1 YY1 transcription factor 4.28e-01 7.08e-05 8.17e-03
PDRG1 p53 and DNA damage regulated 1 5.16e-01 8.53e-05 9.29e-03
LIMCH1 LIM and calponin homology domains 1 5.08e-01 9.07e-05 9.36e-03
DNTTIP2 deoxynucleotidyltransferase terminal interacting protein 2 3.80e-01 1.23e-04 1.15e-02
GNL2 G protein nucleolar 2 4.32e-01 1.19e-04 1.15e-02
SRGN serglycin 4.33e-01 1.51e-04 1.35e-02
NUCKS1 nuclear casein kinase and cyclin dependent kinase substrate 1 -3.12e-01 1.90e-04 1.62e-02
S100A2 S100 calcium binding protein A2 -5.66e-01 2.17e-04 1.77e-02
ATP1A1 ATPase Na+/K+ transporting subunit alpha 1 -4.78e-01 2.84e-04 2.17e-02
MRTO4 MRT4 homolog, ribosome maturation factor 3.29e-01 2.88e-04 2.17e-02
BTF3 basic transcription factor 3 2.42e-01 3.84e-04 2.43e-02
CCN2 cellular communication network factor 2 3.49e-01 3.62e-04 2.43e-02
FAM166A family with sequence similarity 166 member A -3.92e-01 3.75e-04 2.43e-02
SPINT2 serine peptidase inhibitor, Kunitz type 2 -3.18e-01 3.54e-04 2.43e-02
TGM2 transglutaminase 2 4.20e-01 3.36e-04 2.43e-02
CCT5 chaperonin containing TCP1 subunit 5 2.35e-01 4.34e-04 2.50e-02
PTRH2 peptidyl-tRNA hydrolase 2 3.55e-01 4.13e-04 2.50e-02
VIM vimentin -3.39e-01 4.23e-04 2.50e-02
MT-ND2 mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 2 2.14e-01 4.60e-04 2.58e-02
ILF3 interleukin enhancer binding factor 3 3.70e-01 5.52e-04 3.01e-02
MRPS24 mitochondrial ribosomal protein S24 3.92e-01 6.03e-04 3.20e-02
PPP1R14B protein phosphatase 1 regulatory inhibitor subunit 14B -3.39e-01 6.43e-04 3.32e-02
BIRC5 baculoviral IAP repeat containing 5 -2.67e-01 6.95e-04 3.49e-02
GTPBP4 GTP binding protein 4 3.20e-01 7.53e-04 3.69e-02
TP53 tumor protein p53 -4.72e-01 8.43e-04 4.03e-02
MT-CO1 mitochondrially encoded cytochrome c oxidase I 3.33e-01 9.01e-04 4.21e-02
DAP3 death associated protein 3 3.71e-01 9.39e-04 4.28e-02
PLAU plasminogen activator, urokinase 3.34e-01 1.05e-03 4.58e-02
PSMB5 proteasome 20S subunit beta 5 2.53e-01 1.04e-03 4.58e-02
JMJD1C jumonji domain containing 1C 4.69e-01 1.13e-03 4.80e-02
TPR translocated promoter region, nuclear basket protein 4.31e-01 1.15e-03 4.81e-02
GPATCH4 G-patch domain containing 4 3.40e-01 1.26e-03 4.82e-02
MDH1 malate dehydrogenase 1 -2.80e-01 1.26e-03 4.82e-02
MRPL14 mitochondrial ribosomal protein L14 2.39e-01 1.27e-03 4.82e-02
TIMM13 translocase of inner mitochondrial membrane 13 3.44e-01 1.19e-03 4.82e-02
VDAC1 voltage dependent anion channel 1 2.29e-01 1.28e-03 4.82e-02

Gene Set Enrichment Analysis

The GSEA method was applied for all genes whose knockout resulted in at least 20 significantly differentially expressed genes.

ID Name p-value p-value (adj.) log2 Error ES NES
go:0005509 calcium ion binding 4.55e-05 8.72e-02 5.57e-01 -5.12e-01 -1.95e+00
msig:M5890 HALLMARK_TNFA_SIGNALING_VIA_NFKB 1.33e-04 9.88e-02 5.19e-01 5.97e-01 2.01e+00
go:0042273 ribosomal large subunit biogenesis 2.06e-04 9.88e-02 5.19e-01 5.64e-01 1.97e+00
go:0048285 organelle fission 2.04e-04 9.88e-02 5.19e-01 -4.79e-01 -1.91e+00

Literature Mining

INDRA was used to automatically assemble known mechanisms related to COPS5 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
COPS5 deubiquitinates CD274. 10 / 15
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Although PD-L1 had notable basal ubiquitination, CSN5 abolished ubiquitination of PD-L1 (XREF_FIG).

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However, our results suggested that CSN5 directly deubiquitinates and stabilizes PD-L1 in cancer cells to escape from immune surveillance.

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CSN5 in turn, prevents the ubiquitination of PD-L1, hinders its degradation and as a result enhances tumor escape from immunosurveillance.

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Jab1 and COPS5 reduces PD-L1 ubiquitination and stabilizes it.

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Deubiquitination and Stabilization of PD-L1 by CSN5

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Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5 regulated deubiquitination of beta-catenin and PD-L1.

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COP9 signalosome complex subunit 5 (CSN5), a JAMM family DUB, deubiquitinates and stabilizes PD-L1, thereby escaping T cell mediated immune surveillance.

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Deubiquitination and Stabilization of PD-L1 by CSN5.

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Another inhibitor, curcumin (XREF_FIG E), inhibits a JAMM DUB CSN5 that deubiquitinates and stabilizes PD-L1, thereby destabilizing PD-L1 in various cancers [XREF_BIBR, XREF_BIBR].

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TNF-alpha within the tumor microenvironment stabilizes PD-L1 expression by means of COP9 signalosome 5 (CSN5) that directly deubiquitinates PD-L1 and impedes degradation of PD-L1.
COPS5 leads to the deubiquitination of BRSK2. 3 / 3
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We provided the evidence that Jab1 promoted the ubiquitination and degradation of BRSK2.

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Moreover, Jab1 promotes polyubiquitination and degradation of BRSK2.

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Intriguingly, Jab1 promoted the ubiquitination and proteasome dependent degradation of BRSK2.
COPS5 deubiquitinates CTNNB1. 2 / 2
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Collectively, the above results demonstrate that PDIA6 contributes to PC progression, which may be associated with CSN5 regulated deubiquitination of beta-catenin and PD-L1.

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Mechanistically, our results indicate that CSN5 can decrease beta-catenin ubiquitination to enhance the protein expression of SCARA5 in HCC cells.
COPS5 deubiquitinates PEA15. 2 / 2
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Here, we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase-dependent manner.

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Here, we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase dependent manner.
COPS5 deubiquitinates CUL4A. 1 / 1
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Figure 4|in vitro deneddylation assay also demonstrated that CSN could de-ubiquitinat Cul4a
COPS5 leads to the deubiquitination of CDKN1B. 1 / 1
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P27 ubiquitination and degradation is enhanced by JAB1 binding as well as by phosphorylation on Thr187.
COPS5 deubiquitinates STK11. 1 / 1
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Mechanistically, we found that CSN5 directly interacted and deubiquitinated LKB1 for its stabilization in cardiomyocytes.
COPS5 deubiquitinates ZEB1. 1 / 1
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CSN5 deubiquitinates ZEB1 by interacting with it directly, which increases ZEB1 stability [XREF_BIBR, XREF_BIBR].
COPS5 leads to the deubiquitination of MDM2. 1 / 1
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The protein CSN5, a part of the COP9 signalosome and a regulator of cell cycle proteins such as p27, has been shown to increase p53 proteasomal degradation by promoting p53 nuclear export and decreasing MDM2 auto-ubiquitination and degradation XREF_BIBR.
COPS5 deubiquitinates SNAI1. 1 / 1
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For instance, deubiquitination of HSP70 and Snail by CSN5 were reported to modulate exosomal protein sorting and to enhance cancer cell invasion and migration, respectively.
COPS5 deubiquitinates HSPA. 1 / 1
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For instance, deubiquitination of HSP70 and Snail by CSN5 were reported to modulate exosomal protein sorting and to enhance cancer cell invasion and migration, respectively.
COPS5 leads to the deubiquitination of SNAIL. 1 / 1
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COPS5 has also reported to suppress the SNAIL ubiquitination by inhibiting the binding of SNAIL with beta-Trcp, an E3 ligase [XREF_BIBR].
COPS5 leads to the deubiquitination of TP53. 1 / 1
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The protein CSN5, a part of the COP9 signalosome and a regulator of cell cycle proteins such as p27, has been shown to increase p53 proteasomal degradation by promoting p53 nuclear export and decreasing MDM2 auto-ubiquitination and degradation XREF_BIBR.
COPS5 deubiquitinates SNAI2. 1 / 1
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In this study, we identified COP9 signalosome subunit 5 (COPS5) as a deubiquitinating enzyme of SNAIL by using siRNA library screening.
COPS5 leads to the deubiquitination of SMAD4. 1 / 1
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Binding of Jab1 induces the ubiquitination and degradation of Smad4.

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
COPS5 affects CDKN1B
3 1 | 2 87
COPS5 inhibits CDKN1B.
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Overexpression of JAB1 is found to reduce the half-life of p27Kip1 from more than 5 h to 1.4 h [34], and increase the degradation rate of rLHR by 3 fold [45].

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Jab1 promotes p27 degradation through proteolysis and is sensitive to proteasome inhibitors.

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BRSK1 is a novel tumor suppressor in breast cancer which inversely correlated with Jab1 expression, may involve in the restoring Jab1 induced suppression of p27 (Kip1) and may regulate cell cycle through the PI3K and Akt pathway.

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One mechanism may involve JAB1 mediated p27 KIP1 degradation [73].

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Jab1 and CSN5 negatively regulates p27 and plays a role in the pathogenesis of nasopharyngeal carcinoma.

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Mechanistically, Jab1 and p27 were found to interact directly in NPC cells, with Jab1 mediating p27 degradation in a proteasome dependent manner.

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We confirmed that Jab1 over-expression induces the nuclear to cytoplasm translocation of p27 but, to our surprise, treating cells with a p8 siRNA blocked that effect almost completely, indicating that[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In this study, we identified the role of Jab1 mediated p27 degradation in NPC oncogenesis.

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Recent studies have demonstrated that jab1 contributes to carcinoma progression by degrading p27 and Kip1 protein.

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Together, our findings suggest that Jab1 overexpression plays an important role in the pathogenesis of NPC through Jab1 mediated p27 degradation.
COPS5 bound to GFER inhibits CDKN1B. 1 / 1
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Gfer binds to Jab1 and inhibits its destabilization of p27 kip1.
COPS5 bound to CDKN1B inhibits CDKN1B. 1 / 1
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Because Jab1 and CSN5 directly interacts with p27 and promotes p27 degradation in the cytoplasm, Jab1 and CSN5 promotes cell cycle progression [24].
Modified COPS5 inhibits CDKN1B. 1 / 1
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Although JAB1 translocates to the cytoplasm to increase the degradation of p27, it functions also as a transcriptional cofactor for AP-1.
COPS5 activates CDKN1B.
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Ectopic expression of Jab1 and CSN5 induces specific down-regulation of the cyclin dependent kinase (Cdk) inhibitor p27 (p27 (Kip1)) in a manner dependent upon transportation from the nucleus to the cytoplasm.

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Interestingly, JAB1 mediated p27 degradation was not impaired when S-phase kinase interacting protein 2 (Skp2), an F-box protein required for the ubiquitination and consequent degradation of p27, was silenced.

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RT-PCR method was adopted to examine the mRNA expression of the Jab1 and p27kip1 gene in Hep-2 cells which was treated with Jab1 siRNA II.

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By inhibiting Jun activation domain binding protein 1 (Jab1) trastuzumab increases nuclear retention of p27Kip1.

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XREF_BIBR CAPER typically interacts with ESR1 and ESR2 to work as a coactivator of transcription, while JAB1 stimulates the breakdown of the cyclin dependent kinase inhibitor p27Kip1 and regulates HIF by cleaving ubiquitin like proteins.

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Our data indicating a direct interaction of Gfer with Jab1 to restrict Jab1 mediated destabilization of p27 kip1 (XREF_FIG) underscores the importance of a Gfer-Jab1-p27 kip1 pathway not only in the functional maintenance of normal HSCs, but also in the prevention and/or treatment of malignancies.

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This is Jab1 and p27 (kip1) interact with each other, Jab1 accelerate p27 (kip1) from nuclear to cytoplasm through ubiquitin and proteasome pathway.

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Jab1 overexpression may induce p27 downregulation by nuclear export.

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Gfer inhibits Jab1 mediated degradation of p27 kip1 to restrict proliferation of hematopoietic stem cells.

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Although the functional relevance of these mini-complexes remain elusive, XREF_BIBR have revealed that a CSN5 containing mini-complex mediated p27 kip down-regulation in leukemia cells independently of the deneddylation activity of the CSN, suggesting that the mini-complexes may have unique cellular functions.
COPS5 bound to TSPAN1 activates CDKN1B. 1 / 1
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So we pursued the question whether Tspan-1 interacted with some other proteins to affect the ubiquitin (Ub)-proteasome system degrading p27 or interacted with Jab1 to accelerate the transportion of p27 from nucleus to cytoplasm, and then led to accelerate the tumor cells proliferation.
COPS5 bound to UCHL1 activates CDKN1B. 1 / 1
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Binding of UCH-L1 to JAB1 promotes the nuclear export and subsequent proteasomal degradation of the cyclin dependent kinase inhibitor p27 [XREF_BIBR], resulting in increased cell proliferation (XREF_FIG).
COPS5 decreases the amount of CDKN1B.
3 1 | 11
COPS5 decreases the amount of CDKN1B. 10 / 15
3 1 | 6

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No evidence text available

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Jab1 is known to downregulate the expression of the cell cycle inhibitor p27 Kip1 in some cancer models.

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Jab1 was also identified as a direct negative regulator of the CDK inhibitor, p27Kip1, resulting in cell cycle progression (Tomoda et al., 1999).

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Jab1 and COPS5 negatively regulates p27 expression by exporting p27 from the nucleus to the cytoplasm, mediating p27 degradation via the proteasome pathway and promoting cell-cycle progression.

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Thus, disruption of the Jab1 gene not only abolished JAB1 expression but also increased p27, p53 and c-Myc levels and cell death, suggesting that JAB1 is involved in maintaining the integrity and stability of critical regulators of cell proliferation and apoptosis.

bel
Jun activation domain-binding protein 1 (Jab1) was originally identified as a coactivator of activator protein 1 (AP1) transcription and was also shown to promote degradation of the cyclin-dependent kinase inhibitor, p27Kip1.

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Based on these results, we suggest that XLGalpha olf and CSN5 down-regulate the expression of p27 Kip1 cooperatively and this function is controlled by phosphorylation.Furthermore, Galpha s, classifie[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Jab1 promotes degradation of the cyclin-dependent kinase inhibitor p27(Kip1)

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Recently, Jab1 and CSN5, the fifth component of the COP9 signalosome complex, was found to specifically translocate p27Kip1 from the nucleus to the cytoplasm, and reduce the protein level of p27Kip1 by accelerating its degradation.

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In addition, Jab1 silencing by siRNA increased p27 expression levels.
Modified COPS5 decreases the amount of CDKN1B. 5 / 5
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Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation.

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To investigate whether Jab1 overexpression in NPC cells downregulates p27 levels, we transduced those two cell lines with Jab1 adenovirus in the absence or presence of doxycycline and measured Myc-JAB and p27 levels 48 hours after infection.

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Our findings suggest that Jab1 expression is inversely correlated with p27 expression levels, suggesting that Jab1 overexpression contributes to pathogenesis of OSCC by degradating p27 expression.

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In breast cancer, hepatocellular carcinoma, and pancreatic adenocarcinoma, JAB1 is a negative regulator of p27, and high JAB1 expression is associated with poor prognosis and decreased p27 expression.

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Fig. 3 shows that as previously reported, over-expression of Jab1 decreased p27 expression.
COPS5 increases the amount of CDKN1B.
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COPS5 increases the amount of CDKN1B. 5 / 6
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MIF-(50-65) and its variant bound to the MIF binding protein JAB1 and enhanced cellular levels of p27Kip1.

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Furthermore, we found that downregulation of Jab1 induces the cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene.

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Conversely, down-regulation of JAB1 by short interfering RNA substantially increased p27 expression and inhibited progression from G (1) to S phase of the cell cycle.

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Jab1 negatively regulates expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1B (P27) through binding and targeting P27 for ubiquitination and degradation.

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For example, SC deletion of nuclear Jun activation domain binding protein 1 (Jab1) impairs radial sorting by regulating the levels of p27Kip1, which in turn promotes SC exit from the cell cycle and differentiation.
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Also, Jab1 activate the c-jun gene resulted cell proliferation.

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Overexpression of JAB1 promoted the proliferation, migration, and invasion of ESCC cells, and was significantly associated with poor prognosis of ESCC patients.

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In line with this finding, knockdown of CSN5 and CSN4 in cultured cells can significantly reduce the rate of cellular proliferation; this proliferation defect can be fully rescued by forced expression[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Interestingly, Jab1 appears to induce proliferation, as demonstrated in transfection studies using Jab1 overexpressing HCC cell lines and in siRNA experiments blocking Jab1 expression [2].

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Our data demonstrated that Jab1 protein was a vital upstream negative modulation factor of p14ARF, and Jab1 could promote cell proliferation and tumor growth via inhibiting the expression of p14ARF in vivo and in vitro.

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Our previous studies showed that Jab1 and COPS5 was highly expressed in breast cancer and played an essential role in the breast cancer pathogenesis, and that Jab1 knockdown significantly inhibited breast cancer cell proliferation and metastasis.

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It suggests that strong expression of Jab1 not only represents a prognostic marker for malignant transformation but also contributes to cancer cell proliferation and survival.

eidos
C-Jun activation domain-binding protein-1 ( Jab1 ) , which was initially identified as a c-Jun coactivator , is known to modulate cell proliferation , cell cycle , and apoptosis .
| PMC

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Taken together, our results suggest that Trx may regulate cell cycle and growth through a novel modulation of Jab1 mediated proliferation signals, further indicating that Trx may have the ability to control tumor progression.

eidos
Jab1 promotes cell proliferation and inactivates P27 by inducing translocation of P27 from the nucleus to the cytoplasm , which accelerates P27 degradation through the Ub-dependent proteasome pathway and promotes cell cycle progression [ 34 ] .
COPS5 bound to COPS5 activates cell population proliferation. 1 / 1
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XREF_BIBR The proapoptotic function of the E2F1 marked box is facilitated in part through the binding of Jab1 and Csn5, which promotes E2F1 dependent apoptosis but not proliferation.
COPS5 bound to TSPAN1 activates cell population proliferation. 1 / 1
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So we pursued the question whether Tspan-1 interacted with some other proteins to affect the ubiquitin (Ub)-proteasome system degrading p27 or interacted with Jab1 to accelerate the transportion of p27 from nucleus to cytoplasm, and then led to accelerate the tumor cells proliferation.
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We previously showed that the E2F1 binding partner Jab1 and CSN5 promotes E2F1 dependent induction of apoptosis but not proliferation.

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In mammalian cells, knock-down of CSN3 or CSN8 in cultured cells can accelerate cell proliferation [XREF_BIBR, XREF_BIBR], whereas knock-down of CSN5 decreases cell proliferation and causes cell senescence [XREF_BIBR, XREF_BIBR].

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Interestingly, siRNA mediated depletion of Jab1 inhibited cell proliferation and accelerated apoptotic cell death in NPC.

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Depletion of Jab1 inhibits proliferation of pancreatic cancer cell lines.

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Knockdown of either CSN2 or CSN5 dramatically diminished cell proliferation, followed by loss of cell viability.

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Knockdown of CSN5 inhibits the proliferation of human tumor cells XREF_BIBR XREF_BIBR, suggesting that overexpression of CSN5 not only serves as a marker of malignant transformation, but also actually contributes to tumor cell proliferation.

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Knockdown of Jab1 inhibits proliferation and induces apoptosis in hepatocellular carcinoma cells 22.

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Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer.

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The results showed that downregulation of Jab1 significantly inhibited glioma cell proliferation, while overexpression of Jab1 promoted it.

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Depletion of CSN5 suppressed cell proliferation, and induced premature senescence characterized by upregulation of senescence-associated-beta-galactosidase activity and increased expression of CDK inhibitors.

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Knockdown of Jab1 and COPS5 results in the accumulation of p27 in cell nucleus, induces cell-cycle arrest and inhibits cell proliferation.
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Our results show that CSN5 knockdown by small interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell cycle progression in HCC cells in vitro.

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However, there were no significant differences in apoptosis induced by control and Jab1 siRNA.

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Flow cytometric analysis proved that pJAB1 significantly enhanced apoptosis induced by staurosporine, which at least partially depended on the activation of caspase-9 and caspase-3.

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Significantly, inhibition of CSN associated kinase activity or knockdown of CSN5 impairs JFK promoted p53 degradation, enhances p53 dependent transcription, and promotes cell growth suppression, G (1) arrest, and apoptosis.

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As an independent apoptotic mechanism from CSN, CSN5 can enhance apoptosis via activation of transcription factor E2F1.

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Jab1 shRNA treated cells had higher levels of cleaved caspase-3 and gamma-H2AX after cisplatin, IR and UV exposure (XREF_FIG, Top), supporting our hypothesis that Jab1 depletion enhances genotoxic stress induced apoptosis and DNA damage.

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Porcine JAB1 significantly enhances apoptosis induced by staurosporine.

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Interestingly, ectopic expression of JAB1 did not significantly increase apoptosis after addition of TNFalpha, presumably because it can not fully block TNFalpha mediated NF-kappaB activation (see also XREF_FIG).

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Taken together, the mechanism of apoptosis enhanced by JAB1 need to be studied further.

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CSN5 deficient mouse ES cells also displayed dysfunctional proliferation and accelerated apoptosis XREF_BIBR.
COPS5 bound to E2F1 activates apoptotic process. 2 / 2
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In addition, CSN5 specifically interacts with transcription factor E2F1 and enhances E2F1 dependent apoptosis by a mechanism that is independent of deneddylation activity [39].

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We previously showed that the E2F1 binding partner Jab1 and CSN5 promotes E2F1 dependent induction of apoptosis but not proliferation.
COPS5 bound to COPS5 activates apoptotic process. 1 / 1
| 1

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XREF_BIBR The proapoptotic function of the E2F1 marked box is facilitated in part through the binding of Jab1 and Csn5, which promotes E2F1 dependent apoptosis but not proliferation.
| 1 21

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Loss of Jab1 sensitized cells to gamma radiation induced apoptosis and increased spontaneous DNA damage and homologous recombination defects.

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Jab1 and CSN5 inhibits cisplatin- and radiation- induced apoptosis of NPC cells.

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Likewise, Sang et al. have reported that inhibition of Jab1 and COPS5 promoted the apoptosis through p53 related apoptotic pathways in gastric cancer cells.

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Mechanistic investigation revealed that CSN5i-3 inhibited Jab1 expression and increased the expression of apoptosis marker cleaved caspase3 and cell cycle related protein p27 in BT474 and SKBR3 cells.

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Positive staining using the TUNEL assay confirmed that loss of CSN5 could induce germ cell apoptosis.

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Our results showed that knockdown of CSN5 could inhibit proliferation and promote apoptosis of gastric cancer cells.

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Suppression of CSN5 promotes the apoptosis of gastric cancer cells through regulating p53 related apoptotic pathways.

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Thus, in our next experiments we determined whether loss of Jab1 promotes apoptosis of NPC cells in response to DNA damage.

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The knockdown of JAB1 impairs cell cycle progression , increases apoptosis , and its overexpression in human osteosarcoma is correlated with poor prognosis .

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Several targets of Jab1 and CSN5, including p27, p53, c-myc, and cyclin E, were found to be highly expressed in Jab1 and CSN5 -/- embryos, resulting in impaired proliferation and accelerated apoptosis [XREF_BIBR, XREF_BIBR].
COPS5 affects TP53
| 40
COPS5 activates TP53.
| 18
COPS5 activates TP53. 10 / 22
| 18

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The substitution of threonine 155 for valine (T155V) abrogated Jab1 mediated p53 nuclear export, indicating that phosphorylation at this site is essential for Jab1 mediated regulation of p53.

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We therefore used curcumin, a CSN associated kinase inhibitor, to test whether CSN dependent phosphorylation is involved in Jab1 mediated p53 regulation.

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Curcumin prevents Jab1 mediated p53 nuclear export.

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Jab1 induces the cytoplasmic localization and degradation of p53 in coordination with Hdm2.

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The nuclear and cytoplasmic co-localization between COPS5 and p53 suggests a mechanism of COPS5 and p53 interaction and relocalization of p53 from the nucleus to the cytoplasm, and treatment of MG132, a potent proteasome inhibitor, significantly inhibited proteasome dependent protein degradation of p53 and enhanced its levels in cytoplasm, which indicated the degradation of p53 induced by COPS5.

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Phosphorylation of Thr 155 on p53 is required for Jab1 mediated p53 nuclear export.

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Here, we show that phosphorylation at the threonine 155 residue is essential for Jab1 mediated p53 nuclear export.

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When Jab1 was co-expressed with S149D and T150E, their nuclear export pattern was similar to wild-type p53, and was inhibited by curcumin, suggesting that S149 and T150 on p53 are dispensable for Jab1 mediated p53 translocation (XREF_FIG and XREF_SUPPLEMENTARY, panels 1-12 and 21-32).

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Consistently, we found that p53 induced by curcumin or CSN5 RNAi was lack of obvious transcriptional activity.

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Similarly, knockdown of UCH37 and USP14 or b-AP15 treatment rescued p53 protein, induced by COPS5 overexpression, and enhanced the activity of transfected luciferase reporter plasmids for p53, Bax, and p21 expression and protein levels of p53 downstream target genes BAX and p21.
COPS5 inhibits TP53.
| 17
COPS5 inhibits TP53. 10 / 17
| 16

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How Jab1 regulates Rad51 protein and mRNA expression is not completely understood, but it is clear that Jab1 affects the major regulator of Rad51, p53, which was detected in high levels in Jab1 -/- embryos, Jab1 deficient MEFs, and Jab1 knockdown U2OS cells in our study; furthermore, these results have been supported by several other studies that found that JAB1 contributes to the stability of Mdm2 and accelerates p53 degradation and that p53 negatively regulates Rad51 at the transcriptional level through a p53 response element.

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As Jab1 can promote the degradation of p27 [XREF_BIBR] and p53 [XREF_BIBR], we further explored the effect of T83 on these two proteins.

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Jab1 and CSN5 knockdown also impaired proliferation and enhanced apoptosis in these cells regardless of the genotype of the tumor suppressor p53 [XREF_BIBR].

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These results imply that Jab1 can suppress the transcriptional activity of p53, independently of subcellular localization of p53, and possibly via direct binding.

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Inhibition or knockdown of COP9 or CSN5 impairs FBXO42 promoted p53 degradation resulting in enhanced p53 dependent transcription, growth suppression, cell cycle arrest and apoptosis [XREF_BIBR].

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However, when CSN5 siRNA was co-transfected with a p53 specific siRNA, thereby blocking CSN5 siRNA induced p53 accumulation, also diminished the inducible p62 degradation and autophagosome formation in HepG2 cells.

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Asrij and OCIAD1 suppresses CSN5 mediated p53 degradation and maintains mouse hematopoietic stem cell quiescence.

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CSN5 can sequester p53 at the cytoplasm by either directly binding to promote the protein into the ubiquitin-proteasome-mediated protein degradation, or by linking the protein to the COP9 complex [XREF_BIBR, XREF_BIBR].

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JAB1 also promotes the degradation of the tumor suppressor, p53, and the cyclin dependent kinase inhibitor, p27.

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Jab1, a co-activator of AP-1 transcription factor and the fifth subunit of the COP9 signalosome, mediates degradation of the tumor suppressor p53 and p27 (Kip1) and functions as a tumor promoter in different types of human cancer.
COPS5 inhibits mutated TP53. 1 / 1
| 1

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Further, Jab1 could suppress the transcriptional activity of p53 mutants (XREF_SUPPLEMENTARY).
COPS5 increases the amount of TP53.
| 3
COPS5 increases the amount of TP53. 3 / 3
| 3

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Our results demonstrated that CSN5 down-regulation by CSN5 siRNA or curcumin triggered significant p53 protein expression in cancer cells.

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RNA interference (RNAi) of Jab1 restored the levels of the downregulated p53 and Smad4.

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Furthermore, we found that downregulation of Jab1 induces the cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene.
COPS5 decreases the amount of TP53.
| 2
COPS5 decreases the amount of TP53. 2 / 3
| 2

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Thus, disruption of the Jab1 gene not only abolished JAB1 expression but also increased p27, p53 and c-Myc levels and cell death, suggesting that JAB1 is involved in maintaining the integrity and stability of critical regulators of cell proliferation and apoptosis.

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Further investigation on molecular targets revealed that silencing of Jab1 obviously increased the p53 protein level thereby promoting the transcription of ubiquitin ligase Siah1 (Seven in absentia homolog 1), which aggravates the degradation of beta-catenin.
STAT3 affects COPS5
| 27
STAT3 increases the amount of COPS5.
| 18
STAT3 increases the amount of COPS5. 10 / 22
| 12

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Because Stat3 expression in NPC was associated with Jab1 expression, we sought to determine whether the overexpression of Stat3 could enhance Jab1 transcription in NPC cells.

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Besides, upstream activators of Stat3, such as IL-6 and Src, also promote the activation of Jab1 and COPS5 transcription and translation through interacting with Stat3.

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Our studies also revealed that Stat3 functions by binding to Jab1 and COPS5 promoter, promotes its activity and increases Jab1 and COPS5 transcription.

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We further investigated whether an upstream activator of Stat3, the cytokine IL-6, could be driving increased Jab1 expression.

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In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop.

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In summary, the present study demonstrates that the Src and Stat3 and C/EBP signaling pathways positively regulate the expression of the Jab1 oncogene.

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Our previous studies demonstrated that Stat3 [XREF_BIBR] and non coding RNAs [XREF_BIBR] contribute to overexpression of Jab1 and COPS5 in cancer, and highly expressed Jab1 and COPS5 regulates DNA damage response, which confers chemotherapy and radiotherapy resistance to tumor cells [XREF_BIBR].

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We also identify a region whereby CCAAT and enhancer binding protein-beta (C/EBP-beta), signal transducer and activator of transcription-3 (Stat3), and GATA1 induce Jab1 transcription and identify a potential upstream oncogenic signaling molecule that may be key to the regulation of Jab1 expression in cancer.

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Treatment with the cytokine IL-6 resulted in increased Jab1 expression that was blocked by inhibition of Stat3.

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STAT3 knockdown reduces JAB1 promoter activity, JAB1 mRNA, and JAB1 protein expression levels.
Modified STAT3 increases the amount of COPS5. 6 / 6
| 6

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Ectopic overexpression of Stat3 increased transcriptional activity as well as mRNA and protein levels of Jab1.

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Because Stat3 expression in NPC was associated with Jab1 expression, we sought to determine whether the overexpression of Stat3 could enhance Jab1 transcription in NPC cells.

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Ectopic expression of Stat3 in CNE1, CNE2, and HONE1 NPC cells increased Jab1 expression (XREF_FIG and XREF_SUPPLEMENTARY).

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As Jab1 expression in normal mammary epithelial cells is low, we asked whether overexpression of Stat3 could enhance Jab1 transcription in these cells.

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The present study yielded strong evidence that Stat3 overexpression mediates Jab1 overexpression in NPC oncogenesis.

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Expression of exogenous wild type Stat3 increased Jab1 expression, whereas the dominant negative EEE/VV mutation reduced Jab1 protein levels.
STAT3 activates COPS5.
| 7
STAT3 activates COPS5. 7 / 7
| 7

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Our findings that Stat3 positively regulates Jab1 and that Stat3 depletion sensitizes NPC cells to cisplatin suggest that assessing Stat3 and Jab1 levels in NPC patients will help predict the response of their disease to cisplatin treatment and enable the design of individualized treatment strategies for these patients.

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Taken together, these data suggest that C/EBP-beta 2 and Stat3 bind to the Jab1 promoter to increase Jab1 promoter activities.

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Stat3 induced Jab1 transcriptional activation and protein expression.

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Stat3 Induced Jab1 Transcriptional Activation and Protein Expression.

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In addition, transfecting NPC cell lines with ectopic Stat3 significantly increased both the protein and RNA levels of Jab1, and inhibition of endogenous Stat3 expression with specific short interfering RNAs (siRNAs) substantially decreased Jab1 levels and inhibited cell proliferation, indicating that Stat3 positively regulates Jab1 in NPC.

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Second, our recent studies showed that Jab1 and CSN5 is transcriptionally activated by the Stat3 signaling pathway in breast cancer [XREF_BIBR], and in a similar case, our unpublished data seem to indicate that Stat3 positively regulates Jab1 and CSN5 in NPC.

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Stat3 alone increased Jab1 promoter activity, but Stat3 along with C/EBP-alpha and C/EBP-beta synergistically increased Jab1 promoter activity, suggesting that Stat3 interacts with C/EBP on the Jab1 promoter.
STAT3 decreases the amount of COPS5.
| 1
STAT3 decreases the amount of COPS5. 1 / 2
| 1

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In addition, the down-regulation of alpha5-nAChR or/and Stat3 reduced Jab1 and Csn5 expression, while the silencing of alpha5-nAChR or Jab1 and Csn5 inhibited the migration and invasion of NSCLC cells.
STAT3 inhibits COPS5.
| 1
STAT3 inhibits COPS5. 1 / 1
| 1

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Knockdown of Stat3 greatly impairs Jab1 and COPS5 promoter activity and decreases Jab1 and COPS5 RNA and protein levels.
MIF affects COPS5
1 | 1 2 19
MIF inhibits COPS5.
| 1 2 12
MIF inhibits COPS5. 10 / 15
| 1 2 12

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For example, MIF activates mitogen activated protein kinase signaling pathways in NIH/3T3 fibroblasts 13 and endogenous MIF inhibits Jab1 activity and antagonizes Jab1 dependent cell-cycle regulation.

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Given that AP-1 is associated with activation of pro inflammatory responses in numerous immune cell types, an anti-inflammatory and immunosuppressive role for MIF might be expected when intracellular MIF concentrations are at sufficient levels to functionally inhibit Jab1 and CSN5.

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When MIF and JAB1 are bound to each other in various intracellular sites, MIF inhibits the positive regulatory effects of JAB1 on the activity of AP-1.

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Because JAB1 is involved in the regulation of AP1-dependent transcription and the cell cycle, and MIF inactivates JAB1 by binding to it, the cytosolic pool of MIF appears to be engaged in an additional regulatory circle distinct from the MAPK/ERK pathway.

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MIF would thereby inhibit Jab1 enhanced AP-1 transcriptional activity [XREF_BIBR].

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Subsequent functional studies showed that MIF can antagonize several JAB1 and CSN5 based cellular effects.

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MIF inhibits JAB1 activity.

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Bernhagen 's group first identified that MIF negatively regulates the activity of cytosolic Jab1 on both steady-state and stimulus induced AP-1-dependent transcription.

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We conclude that MIF may act broadly to negatively regulate Jab1 controlled pathways and that the MIF-Jab1 interaction may provide a molecular basis for key activities of MIF.

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Intracellular MIF sequesters CSN5 to block AP-1 transcriptional factor activity [XREF_BIBR].
MIF activates COPS5.
| 6
MIF activates COPS5. 6 / 7
| 6

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The absence of MIF in females is associated with enhanced microglial activation and increased localization of JAB1 to the mitochondria in the infarcted brain.

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At low concentrations MIF induces the release of TNF-alpha, IL-12, IL-1beta, and PGE 2 and, in a distinct difference from other " common " cytokines, involves MAPK, Akt, and PI3K activation and regulation of Jab1 and p53 [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

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siRNA knockdown of CSN5 and JAB1, a tumor marker and MIF binding protein, showed that JAB1 controls autocrine MIF mediated Akt signaling by inhibition of MIF secretion.

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MIF can modulate the activator protein-1 (AP-1) pathway and cell cycle progression through interaction with the coactivator and COP9 signalosome (CSN) component JAB1 and CSN5 [20].

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Interestingly, MIF was shown to modulate CSN5 function and subsequent CSN5 dependent effects on p27 degradation, JNK activation and AP-1-mediated transcription.

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Jab1 and CSN5 dependent stabilisation of HIF-1alpha is enhanced by MIF, leading to the subsequent activation of hypoxia responsive genes.
MIF increases the amount of COPS5.
| 1
MIF increases the amount of COPS5. 1 / 1
| 1

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In contrast, overexpression of JAB1 led to an inhibition of the stimulation of phospho-ERK1/2 by MIF and to an apparent enhancement of the inhibition of phospho-ERK1/2 by higher MIF concentrations as [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
MIF decreases the amount of COPS5.
1 |
MIF decreases the amount of COPS5. 1 / 1
1 |

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MIF colocalizes with Jab1 in the cytosol, and both endogenous and exogenously added MIF following endocytosis bind Jab1. MIF inhibits Jab1- and stimulus-enhanced AP-1 activity
COPS5 affects AP1
| 1 2 14
COPS5 activates AP1.
| 1 2 11
COPS5 activates AP1. 10 / 18
| 1 2 11

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Furthermore, overexpression of hAPH2 could increase apoptosis of COS-7 cells and negatively regulate JAB1-induced activation of AP-1 in a concentration dependent manner.

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In this study, we found that hAPH2 could antagonize the activation of AP-1 induced by JAB1 in COS-7 cells, but we are not able to find whether this negative effect on AP-1 activity is JAB1 dependent o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Furthermore, overexpression of hAPH2 could increase apoptosis of COS-7 cells and negatively regulate JAB1 induced activation of AP-1 in a concentration dependent manner.

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Given that hAPH2 could interact with JAB1, we further investigated whether hAPH2 could modulate JAB1 induced AP-1 activity.

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The binding of MIF with JAB1 / CSN5 also modulates AP-1 activity and cell proliferation by inactivation of p53 [ 8] .

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MIF would thereby inhibit Jab1 enhanced AP-1 transcriptional activity [XREF_BIBR].

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HPO site directed mutants (Cys and Ser) at active sites, which lost sulfhydryl oxidase activity, could not increase c-Jun phosphorylation and failed to potentiate JAB1 mediated AP-1 activation.

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Interestingly, JAB-1 does not appear to potentiate AP-1 activity after TCR stimulation (unpublished data).

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Furthermore, the data indicated that E9730 appeared to enhance Jab1 induced AP-1 activity in a concentration dependent manner and Jab1 may be involved in the intracellular signaling transduction from E9730 to AP-1.

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MIF inhibits JAB1 and CSN5 mediated AP-1 activity and reduces JNK activity stimulated by JAB1 and CSN5.
COPS5 inhibits AP1.
| 3
COPS5 inhibits AP1. 3 / 3
| 3

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As is shown in Fig. 9, group 1 that is transfected with AP-1-Luciferase and pCMV-Myc vector showed nearly no activity of the luciferase reporter, while overexpression of c-jun (group 2) and Jab1 (grou[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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We have demonstrated that CARP repressed JAB1 mediated AP-1 activation and enhanced p27 nuclei accumulation XREF_BIBR.

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The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx.
COPS5 affects JUN
1 | 1 15
COPS5 activates JUN.
1 | 1 11
COPS5 activates JUN. 10 / 15
| 1 11

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When transfected into HeLa cells, p38 (JAB1) potentiates the transcriptional activity of c-Jun, but co-transfection with rLHR prevents this effect.

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Overexpression of CSN5 can not rescue c-Jun destabilization in siCSN1.

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Human JAB1 (Jun activation domain binding protein 1) was first described as a coactivator of c-Jun and Jun D. JAB1 enhances the ability of c-Jun and Jun D to activate transcription by stabilizing comp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Human JAB1 (Jun activation domain binding protein 1) was first described as a coactivator of c-Jun and Jun D. JAB1 enhances the ability of c-Jun and Jun D to activate transcription by stabilizing comp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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For instance, JAB1 enhances c-Jun transactivation by enhancing binding to their cognate DNA sequences [39,40].

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COPS5 (official gene symbol of CSN5) is responsible for the deneddylation activity of the COP9 signalosome, and also known as Jab1 to activate c-Jun (Jun-activating and binding protein).

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CSN5 enhances AP-1-mediated transcriptional activation by stabilizing complexes of the transcription factors c-Jun or JunD [9].

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Jab1 co-activation of c-Jun is abrogated by the serine 10-phosphorylated form of p27Kip1.

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In addition, VDUP1 inhibited JAB1 mediated activator protein-1 activation and cell proliferation.

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Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun.
COPS5 activates JUN. 1 / 1
1 |

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Jab1 activates c-Jun amino-terminal kinase (JNK) activity and enhances endogenous phospho-c-Jun levels, and MIF inhibits these effects. MIF also antagonizes Jab1-dependent cell-cycle regulation by increasing p27Kip1 expression through stabilization of p27Kip1 protein
COPS5 inhibits JUN.
| 3
COPS5 inhibits JUN. 3 / 3
| 3

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In CSN5 knockdowns c-Jun destabilization was rescued by CSN5 overexpression, demonstrating the substrate receptor role of CSN5.

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Loss-of-function studies, using Jab1 small interfering RNA, demonstrated that Jab1 knockdown blocked PAR-2-induced activator protein-1 activation.

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MIF can also interact with intracellular binding proteins, such as JUN-activation domain-binding protein 1 (JAB1), through which it can block the activity of JNK pathway and its target transcription factor AP-1 (128).
| PMC
COPS5 increases the amount of JUN.
| 1
COPS5 increases the amount of JUN. 1 / 2
| 1

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Jab1 also stabilizes certain proteins, such as hypoxia inducible factor 1alpha and c-Jun, and potentiates c-Jun and MYC transcription, which is responsible for the transcriptional activation of genes involved in cell proliferation, angiogenesis, and invasion.
COPS5 affects RAD51
| 20
COPS5 activates RAD51.
| 11
COPS5 activates RAD51. 10 / 11
| 11

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Moreover, we discovered that Jab1 positively regulated Rad51 in p53 dependent manner and that overexpression of Rad51 conferred cellular resistance to adriamycin and cisplatin in Jab1 deficient cells.

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Furthermore, Jab1 positively regulates Rad51 in NPC, explaining why Jab1 depletion sensitizes NPC cells to cisplatin, IR and UV.

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In this study, we used three NPC cell lines (CNE1, CNE2 and HONE1) to investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, cellular response to treatment with DNA damaging agents such as cisplatin, ionizing radiation (IR) and ultraviolet (UV) radiation.

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Recently, we found that the aberrant activation of Jab1 overexpression is correlated with a lower survival rate in NPC patients 14 and that Jab1 positively regulates the DNA repair gene Rad51 and contributes to NPC cells ' response to radiotherapy and cisplatin 15.

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In this study, we used three NPC cell lines (CNE1, CNE2, and HONE1) to investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, cellular response to treatment with DNA damaging agents such as cisplatin, ionizing radiation (IR) and ultraviolet (UV).

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Recently, we found that Jab1 and Csn5 positively regulates the DNA repair gene Rad51 and contributes to radiation resistance in NPC; Therefore, we hypothesized that Jab1 and Csn5 participates in the process of recurrence after radical radiotherapy in NPC patients.

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Liu et al 's study 29 showed that Jab1 contributes to chemoresistance in breast cancer by regulating Rad51, and patients with Jab1 overexpression exhibited a poor prognosis.

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The current finding that Jab1 positively regulates Rad51 and contributes to the response of NPC cells to cisplatin, IR and UV suggests that assessing the Jab1 level in patients may help predict response to cisplatin and radiation treatments, allowing the design of individualized treatment strategies for patients with NPC.

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In the current study, we investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, the cellular response of breast cancer to chemotherapy with adriamycin and cisplatin.

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Transient knockdown of JAB1 by siRNA decreased Rad51 promoter activity in U2OS (p53 WT) cells but not in Saos-2 (p53-null) cells (XREF_FIG).
COPS5 increases the amount of RAD51.
| 6
COPS5 increases the amount of RAD51. 4 / 4
| 4

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Inhibition of Jab1 and COPS5 not only decreases Rad51 level but also impaired its activity, resulting in an increase in cell apoptosis after DNA stimulus.

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Jab1 and CSN5 knockdown not only decreased the level of Rad51 but also affected its activity.

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These results suggested that Jab1 knockdown causes reduction in Rad51 gene expression, leading to a decreased ability of cells to repair DNA lesions through a homologous recombination pathway.

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Jab1 knockdown not only decreased the protein level of Rad51 but also affected its repair function, as shown on XREF_FIG, which compares a reduced Rad51 foci formation in Jab1 siRNA treated cells with the Rad51 foci in control siRNA treated cells after gamma-IR.
Modified COPS5 increases the amount of RAD51. 2 / 2
| 2

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We demonstrated that knocking down Jab1 expression in these NPC cells sensitized them to cisplatin, IR and UV radiation, and conversely, overexpression of Jab1 contributes to cisplatin and irradiation resistance in NPC cells by positively regulating the levels of the DNA repair gene Rad51.

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Conversely, overexpression of Jab1 and CSN5 contributed to cisplatin and radiation resistance in NPC cells by positively regulating the levels of expression of the DNA repair gene Rad51.
COPS5 decreases the amount of RAD51.
| 3
COPS5 decreases the amount of RAD51. 3 / 3
| 3

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These results suggest that depletion of Jab1 and CSN5 reduces the expression of Rad51, leading to reduce ability of NPC cells to repair DNA lesions.

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These results suggest that Jab1 depletion reduces the expression of Rad51, leading to a reduction in the ability of cells to repair DNA lesions and an increase in apoptosis, thus sensitizing NPC cells to cisplatin, IR and UV.

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Furthermore, Jab1 depletion not only decreased the level of Rad51 but also affected its activity, as indicated by loss of Rad51 causing extensive chromosomal breaks, leading to apoptosis.
ERBB2 affects COPS5
| 15
ERBB2 increases the amount of COPS5.
| 10
ERBB2 increases the amount of COPS5. 9 / 12
| 9

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In this study, we reported that expression of Jab1 was stimulated by HER-2 and neu oncogene via transcriptional activation.

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Similarly, HER-2 and neu was found to activate Jab1 and CSN5 expression through the AKT and bet-catenin pathway [XREF_BIBR].

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Inhibition of HER-2 and neu activity by Herceptin or AG825 significantly attenuated Jab1 expression in HER-2 and neu-overexpressing MDA-MB-453 cells.

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In addition, ErbB2 has been reported to transcriptionally activate expression of the Wnt pathway target gene Jab1 via an Akt and beta-catenin pathway in breast cancer cells.

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HER-2 and neu transcriptionally activates Jab1 expression via the AKT and beta-catenin pathway in breast cancer cells.

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Taken together, our results suggest that HER-2 and neu transcriptionally activates Jab1 expression to promote proliferation of breast cancer cells.

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The regulation of Jab1 expression by HER2 through the AKT pathway is of great interest, and further studies could strengthen our understanding on the role of Jab1 in the tumorigenic process.

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We also demonstrated that HER-2 and neu increased beta-catenin and TCF-mediated Jab1 expression via the AKT signaling pathway because chemical inhibitor or dominant negative mutant of AKT effectively attenuated the stimulatory action of HER-2 and neu.

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HER-2 enhances Jab1 and COPS5 promoter activity and increases Jab1 and COPS5 expression through AKT and beta-catenin pathway.
Modified ERBB2 increases the amount of COPS5. 1 / 1
| 1

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On the contrary, ectopic expression of HER-2 and neu stimulated Jab1 expression in MCF-7 cells.
ERBB2 activates COPS5.
| 4
ERBB2 activates COPS5. 4 / 5
| 4

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In contrast to our data and other interaction effects, these studies concluded that Her2 mediated Jab1 regulation occurs at the transcriptional level.

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Promoter activity assay suggested that HER-2 and neu oncogene upregulated Jab1 via transcriptional activation.

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HER2 has been found to stimulate Jab1 transcriptional activity in NIH3T3 cells stably expressing the HER2 receptor [XREF_BIBR].

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Also, HER-2 and neu activity causes mislocation of p27 and Jun activation domain binding protein 1 (JAB1), an exporter of p27, into the cytoplasm, thereby facilitating p27 degradation.
ERBB2 inhibits COPS5.
| 1
ERBB2 inhibits COPS5. 1 / 1
| 1

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Promoter deletion and mutation analysis indicated that HER-2 and neu stimulated Jab1 via the T cell factor (TCF) binding site located at the -380/-368 region of the human Jab1 promoter.
COPS5 affects NFkappaB
| 14
COPS5 activates NFkappaB.
| 8
| 6

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It has to be noted though that the effect of Csn5 and JAB1 on NF-kappaB seems to depend on the cell type and cellular context, as loss of JAB1 was also reported to reduce NF-kappaB activity, e.g. in thymocytes [XREF_BIBR] or synovial fibroblasts of rheumatoid arthritis patients [XREF_BIBR].

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In their study, the authors found that depletion of CSN5 increased NF-kappaB activity.

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Moreover, CSN5 silencing inhibited the secretion of TGF-beta, IL-1beta and IL-6 and the transcriptional activity of transcription factor NF-kappaB and Twist in human colorectal cancer cells.

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However, Jab1 can activate NF-kappaB through Bcl-3 without forming a detectable complex with Bcl-3 and p50, suggesting that Jab1 transiently interacts with a complex of Bcl-3 and p50 [7].

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Knock-down of Csn5 and JAB1 clearly enhanced basal NF-kappaB activity and improved cell survival under stress.

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Mechanistically, Csn5 KO potentiated NF-kappaB signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1alpha levels were reduced.
COPS5 bound to BCL3 activates NFkappaB. 1 / 1
| 1

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Jab1 and CSN5 binds to Bcl-3 to enhance NF-kappaB, p50, and DNA complex formation and may link NF-kappaB and AP-1 gene transcription [XREF_BIBR].
COPS5 bound to MIF activates NFkappaB. 1 / 1
| 1

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Consistent with its diverse functions and the large array of cell types that produce it, the downstream effects of MIF are extensive : MIF activates MAPK signaling pathways 16, promotes LPS stimulation through TLR4 17, interacts with Jab1 to increase transcription of AP-1 target genes 18, and activates NF-kappaB 19.
COPS5 inhibits NFkappaB.
| 6
| 6

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Further, siRNA mediated repression of CSN5, a subunit of the COP9 signalosome responsible for deneddylation of Cul-1, partially reversed HPC mediated inhibition of NF-kappaB.

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Gene suppression of the CSN subunit JAB1 and Csn5 augmented constitutive NF-kappaB activity, while ectopic expression of JAB1 reduced it.

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Furthermore, CSN5 silencing enhanced TNF-alpha-induced IkappaB-alpha degradation and NF-kappaB activity in luciferase reporter assays.

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JAB1 silence induced Ik-Balpha degradation, enhanced NF-kappaB activity, increased the TNF-a-induced expression of adhesion molecules (CCL2, ICAM-1, VCAM-1) and induced monocytes arrest rate on inflamed endothelium in vitro [XREF_BIBR].

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The work of others has demonstrated that CSN5 is a negative regulator of NF-kappaB and a decrease in CSN5 increases nuclear NF-kappaB thereby stimulating proliferation.

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This notion was supported by reporter gene assays for NF-kappaB activity, which revealed that ectopic expression of JAB1 significantly reduces basal NF-kappaB activity, while suppression of endogenous JAB1 by RNA interference leads to a prominent up-regulation (XREF_FIG).
COPS5 affects cisplatin
| 16
COPS5 activates cisplatin.
| 13
| 13

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Depletion of Jab1 by siRNA, which leads to inhibition of proliferation, enhanced cisplatin activity in NPC.

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By contrast, exogenous Jab1 expression enhanced the resistance of NPC cells to cisplatin, IR and UV radiation.

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In conclusion, we demonstrated that Jab1 contributes to the sensitivity and resistance of NPC cells to cisplatin and irradiation.

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By contrast, exogenous Jab1 expression enhanced the resistance of breast cancer cells to adriamycin and cisplatin.

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Moreover, Jab1 depletion enhanced the antitumor effects of cisplatin in NPC cells.

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On the basis of our previous findings, we hypothesized that Jab1 contributes to cisplatin, IR and UV resistance.

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By contrast, exogenous Jab1 expression enhanced the resistance of NPC cells to cisplatin, IR and UV Moreover, we provide a mechanism by which Jab1 positively regulated Rad51 through p53 dependent pathway, and increased ectopic expression of Rad51 conferred cellular resistance to cisplatin, IR and UV in Jab1 deficient cells.

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The current finding that Jab1 positively regulates Rad51 and contributes to the response of NPC cells to cisplatin, IR and UV suggests that assessing the Jab1 level in patients may help predict response to cisplatin and radiation treatments, allowing the design of individualized treatment strategies for patients with NPC.

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Recently, we found that the aberrant activation of Jab1 overexpression is correlated with a lower survival rate in NPC patients 14 and that Jab1 positively regulates the DNA repair gene Rad51 and contributes to NPC cells ' response to radiotherapy and cisplatin 15.

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Similarly, the levels of phospho-Chk2, a key molecule in transducing DNA damage signals, were increased after cisplatin and UV exposure regardless of whether the cells were treated with Jab1 siRNA (although the phospho-Chk2 levels were higher in Jab1 deficient cells).
COPS5 inhibits cisplatin.
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In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage.

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We firstly tested whether inhibition of Jab1 enhances the antitumor effects of cisplatin by MTT assay.

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In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin.
COPS5 affects cell cycle
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COPS5 activates cell cycle.
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In contrast, Jab1 does not synergize with E2F1 to promote cell cycle entry.

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Our group recently found that Jab1 contributes to NPC tumorigenesis and resistance to radiotherapy by promoting NPC cell growth, dysregulating NPC cell cycle progression, and inhibiting radiation induced apoptosis XREF_BIBR, XREF_BIBR, XREF_BIBR.

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As Jab1 modulates the cell cycle in other cell types, we investigated Schwann cell number, survival, and cell cycle progression in Jab1 -/- nerves.

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CSN5 silencing inhibits invasion and arrests cell cycle progression in human colorectal cancer SW480 and LS174T cells in vitro.

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Because Jab1 and CSN5 directly interacts with p27 and promotes p27 degradation in the cytoplasm, Jab1 and CSN5 promotes cell cycle progression [24].

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Jab1 (Jun activation domain binding protein 1), integrated into COP9 signalosome complex (CSN), induces protein instability of many tumor suppressors and cell cycle regulators and is therefore a novel target in cancer therapy.

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Our results show that CSN5 knockdown by small interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell cycle progression in HCC cells in vitro.

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Dysregulation of COPS5 activity has been shown to contribute to oncogenesis through its function in cell proliferation [XREF_BIBR], cell cycle progression [XREF_BIBR], and cell chemo- and radio-resistance [XREF_BIBR, XREF_BIBR], that are mediated by the various target molecules such as MDM2, p27, HIF-1alpha, and AP-1 [XREF_BIBR].

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The knockdown of JAB1 impairs cell cycle progression , increases apoptosis , and its overexpression in human osteosarcoma is correlated with poor prognosis .

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We also found that knockdown of CSN5 remarkably suppressed cell growth by inducing cell cycle arrest and apoptosis promotion in NSCLC cells.
COPS5 inhibits cell cycle.
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Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis.

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As the cellular abundance of p27 is an indicator of cell cycle, we thus reviewed relative articles to find whether the cell cycle arrest effect caused by COPS5 or COPS6 inhibition was p27 dependent.

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CSN5 and Jab1 elimination inhibited progression of the cell cycle at multiple points, seemed to initiate p53 independent senescence and increased the ploidy of cells.

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We found that in Schwann cells, cell cycle arrest caused by loss of COPS5 could be restored by genetic depletion of p27 [18].

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The co-transfection of Jab1 with BRSK2 reduced cell cycle arrest at G2/M phase from 30% to 19%.
COPS5 affects BMP
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COPS5 inhibits BMP.
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COPS5 inhibits BMP. 7 / 7
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Thus, Jab1 might negatively regulate BMP signaling during chondrocyte differentiation in part by sequestering Smad1/5/8 away from Acvr1.

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Together, our study demonstrates that Jab1 represses chondrocyte hypertrophy in vivo, likely in part by downregulating BMP signaling and Runx2 activity.

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Furthermore, Jab1 represses chondrocyte hypertrophy in vivo, likely in part by down-regulating BMP signaling.

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By degrading Smad4 or Smad7, Jab1 can repress or increase TGF-beta and BMP signaling, respectively, in vitro.

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Jab1 cKO limb bud cells had significantly decreased BMP reporter activity compared with wild-type littermate controls (XREF_FIG).

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In contrast, previously we have shown that Jab1 represses BMP signaling in differentiating chondrocytes, using a Col2a1-Cre transgene to achieve chondrocyte specific Jab1 knockout.

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Jab1 has been reported to interact with Smad5 and cause an attenuation of BMP dependent transcriptional responses, suggesting that Jab1 might act as an inhibitor of BMP signaling XREF_BIBR.
COPS5 bound to SMAD5 inhibits BMP. 1 / 1
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Although Jab1 can interact with the bone morphogenetic protein (BMP) downstream effector Smad5 to repress BMP signaling in vitro, the role of Jab1 in BMP mediated skeletogenesis in vivo is still poorly understood.
COPS5 activates BMP.
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COPS5 activates BMP. 7 / 7
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Thus, aberrant accumulation of Jab1 resulting from inactivation of the CUL4B E3 ligase may enhance BMP signaling by decreasing levels of the inhibitor Smad7.For the structural basis, Jab1 ubiquitinati[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Jab1 likely promotes Sox9 and BMP signaling activity during early limb development.

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As shown in XREF_FIG, Panels A and B, we observed a reduced level of Jab1 protein and an elevated level of BMP induced alkaline phosphatase mRNA, respectively, in C2C12 cells treated with Jab1 siRNA.

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And the upregulation of BMP signaling in response to CUL4B silencing could be partially rescued by co-depletion of Jab1, thus restoring BMP signaling to a level not significantly different from that o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Together, these data establish Jab1 as an ubiquitination target for the CUL4B ubiquitin ligase complex.In addition to its role in deneddylation [32,33], Jab1 and CSN5 has been shown to bind to Smad7, [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Consistent with the results shown in Fig. 1 A and B, the transfection of pFLAG-CUL4B could almost completely rescue the BMP signaling in RNAi mediated CUL4B depletion cells, whereas FLAG-CUL4A or FLAG[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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These observations suggest that Jab1 may promote BMP signaling in OPCs during early limb development.

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We show that JAB1 binds directly to the HLH domain of HAND2 and increases HAND2 transcription stimulating activity.

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Moreover, CSN subunits may act as monomers, and CSN5 can positively regulate several transcription factors, including NFkappaB, JUN/AP-1, Hif1alpha, and E2F1.

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Significantly, inhibition of CSN associated kinase activity or knockdown of CSN5 impairs JFK promoted p53 degradation, enhances p53 dependent transcription, and promotes cell growth suppression, G (1) arrest, and apoptosis.

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CSN5, the fifth CSN subunit, was initially identified as c-Jun-activation-domain binding protein-1 (Jab1) that mediates AP-1-dependent gene transcription via stabilization of c-Jun [4,5].

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As mentioned above, CSN5 was discovered as c-Jun-activation-domain binding protein JAB1, mediating AP-1-dependent gene transcription by stabilization of c-Jun [4,5].

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Human JAB1 (Jun activation domain binding protein 1) was first described as a coactivator of c-Jun and Jun D. JAB1 enhances the ability of c-Jun and Jun D to activate transcription by stabilizing comp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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This includes defining mechanisms whereby LFA-1 engagement enhances transcriptional activation of numerous genes by regulating its association with transcription modulators such as JAB-1, and through interaction with other gene activating signaling complexes such as JAK-STATs.

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Moreover, CSN5 silencing inhibited the secretion of TGF-beta, IL-1beta and IL-6 and the transcriptional activity of transcription factor NF-kappaB and Twist in human colorectal cancer cells.

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JAB1 associates with beta2 integrins in lymphocytes and, upon alpha L beta 2 engagement, translocates into the nucleus and enhances c-Jun-driven transcription [2].

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CSN5 enhances AP-1-mediated transcriptional activation by stabilizing complexes of the transcription factors c-Jun or JunD [9].
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Furthermore, JAB1, a transcriptional coactivator that increases the specificity of AP-1 transcription factors, interacts with both c-Jun and JunD to potentiate transcription (Claret et al., 1996).

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The Jun activation-domain binding protein 1 (Jab1) is initially identified as a coactivator of activator protein (AP-1) transcription factor and found a component of the COP9 signalosome (CSN) complex, contained modulating signal transduction, gene transcription, and protein stability.
COPS5 bound to KMT2D activates transcription, DNA-templated. 1 / 1
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Intracellularly, ALR binds to Jun Activation domain Binding protein 1 (JAB 1) and potentiates Activator Protein-1 (AP-1) transcription activation pathway utilizing its sulfhydryl oxidase activity XREF_BIBR, XREF_BIBR.
COPS5 bound to TGFB activates transcription, DNA-templated. 1 / 1
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Jab1 and COPS5 directly binds to Smad4 and degrades it through the proteasome pathway and thus attenuate TGF-beta mediated gene transcription, whereas its degradation of Smad7 results in enhanced TGF-beta signaling effects.
COPS5 bound to JUND activates transcription, DNA-templated. 1 / 1
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Furthermore, JAB1, a transcriptional coactivator that increases the specificity of AP-1 transcription factors, interacts with both c-Jun and JunD to potentiate transcription (Claret et al., 1996).
COPS5 affects COPS5
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COPS5 increases the amount of COPS5.
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COPS5 increases the amount of COPS5. 4 / 5
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This suggests that pJab1 plasmid specifically targeting Jab1 gene expression could be an effective therapy for human laryngeal carcinoma.

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To address the role of Jab1 and Sec6 in more depth, further research is needed to investigate how Jab1 modulates p27 phosphorylation at Thr157 and Sec6 regulates Jab1 expression.In a previous study, w[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Thus, disruption of the Jab1 gene not only abolished JAB1 expression but also increased p27, p53 and c-Myc levels and cell death, suggesting that JAB1 is involved in maintaining the integrity and stability of critical regulators of cell proliferation and apoptosis.

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Silencing of CSN5 mRNA using siRNA decreased the endogenous protein level of CSN5 and activated L-type Ca (2+) channels expressed in COS7 cells.
Modified COPS5 increases the amount of COPS5. 2 / 2
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Nevertheless, it appears that the obtained reductions in JAB1 levels have lowered cellular JAB1 levels below a critical threshold value that is otherwise necessary to maintain JAB1 function in positiv[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Interestingly enough, in CSN8-null cells, CSN5 protein level did not diminish XREF_BIBR, consistent with the notion that full upregulation of cyclin E requires loss of CSN5, in addition to the inactivation of the CSN complex.
COPS5 inhibits COPS5.
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COPS5 inhibits COPS5. 3 / 3
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In CSN5 knockdowns c-Jun destabilization was rescued by CSN5 overexpression, demonstrating the substrate receptor role of CSN5.

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We next examined whether suppression of Jab1 expression could increase the sensitivity of NPC cells to cisplatin, IR and UV by knocking down Jab1 in HONE1 and CNE2 cells.

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Supporting CSN5 specific inhibition on mRNA levels (XREF_FIG), we found a significant reduction only in CSN5 protein levels while other CSN subunits (e.g. CSN1, CSN3 and CSN8) showed little or no change (XREF_FIG).
COPS5 activates COPS5.
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COPS5 activates COPS5. 3 / 3
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Overexpression of CSN5 produces a free CSN5 protein pool, which stimulates the degradation of EB1.

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Analysis of EGFR and Jab1 expression in a cohort of invasive breast tumors by tissue microarray and immunohistochemistry confirmed a relationship between EGFR and increased nuclear Jab1 within the ERalpha - subset (n = 154, P = 0.019).

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In anaplastic carcinoma, the incidence of jab1 overexpression increased significantly, strongly indicating the contribution of jab1 to thyroid carcinoma developing an extremely aggressive phenotype th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
COPS5 decreases the amount of COPS5.
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COPS5 decreases the amount of COPS5. 2 / 2
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Here, we report that transcription coactivator CSN5 interacts with the intracellular II-III linker of the alpha 1C subunit of cardiac L-type Ca 2+ channel in vivo and inhibits channel activity.Overexp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Immunoblot analysis revealed that both CSN5 siRNA-1 and siRNA-2 efficiently repressed expression of CSN5 without affecting that of CSN1 and CSN8, suggesting that knockdown of CSN5 does not cause disru[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
COPS5 affects HIF1A
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COPS5 activates HIF1A.
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COPS5 activates HIF1A. 3 / 8
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Second, in a manner independent of the CSN holocomplex, CSN5 (or a CSN5 containing small complex) promotes cell proliferation by inducing p27 degradation [22,23] and HIF1-alpha stabilization [41].

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While Jab1 promotes HIF-1alpha stability and transactivation, p53 degrades HIF-1a and decreases its transactivation.

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However, in contrast to the studies involving MIF regulation of the SCF complex resulting in enhanced degradation and decreased stability of p27 and Cdc25A proteins, MIF and CSN5 regulates HIF-1alpha turnover resulting in enhanced stability and decreased degradation of HIF-1alpha.
COPS5 activates HIF1A. 2 / 2
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Moreover, Jab1-enhanced transcriptional activity of HIF-1 under hypoxia led to increase the expression of VEGF, a major HIF-1 target gene. Furthermore, Jab1 increased HIF-1alpha protein levels, which was due to the enhanced HIF-1alpha stability

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Jab1 acts as a cofactor to stimulate transcription of genes regulated by NFKB, AP1 and HIF1 transcription factors
COPS5 increases the amount of HIF1A.
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COPS5 increases the amount of HIF1A. 2 / 3
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Furthermore, Jab1 increased HIF-1alpha protein levels, which was due to the enhanced HIF-1alpha stability.

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Moreover, Jab1-enhanced transcriptional activity of HIF-1 under hypoxia led to increase the expression of VEGF, a major HIF-1 target gene. Furthermore, Jab1 increased HIF-1alpha protein levels, which was due to the enhanced HIF-1alpha stability
COPS5 inhibits HIF1A.
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COPS5 inhibits HIF1A. 1 / 1
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