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: 365 retrieved on 2023-02-19

DepMap Analysis

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

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

DepMap Correlations

Symbol	Name	DepMap Correlation	Evidence	CCLE Correlation	CCLE Z-score	CCLE p-value (adj)
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

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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.

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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.

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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.

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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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COPS5 has also reported to suppress the SNAIL ubiquitination by inhibiting the binding of SNAIL with beta-Trcp, an E3 ligase [XREF_BIBR].

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COPS5 affects CDKN1B

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COPS5 inhibits CDKN1B.

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COPS5 inhibits CDKN1B. 10 / 53

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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.

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COPS5 bound to GFER inhibits CDKN1B. 1 / 1

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Gfer binds to Jab1 and inhibits its destabilization of p27 kip1.

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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].

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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.

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COPS5 activates CDKN1B.

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COPS5 activates CDKN1B. 10 / 23

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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.

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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.

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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).

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COPS5 decreases the amount of CDKN1B.

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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.

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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.

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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.

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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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COPS5 affects cell population proliferation

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COPS5 activates cell population proliferation.

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COPS5 activates cell population proliferation. 10 / 56

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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.

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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 .

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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.

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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 ] .

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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.

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COPS5 bound to TSPAN1 activates cell population proliferation. 1 / 1

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COPS5 bound to E2F1 activates cell population proliferation. 1 / 1

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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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COPS5 inhibits cell population proliferation.

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COPS5 inhibits cell population proliferation. 10 / 19

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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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COPS5 affects apoptotic process

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COPS5 activates apoptotic process.

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COPS5 activates apoptotic process. 10 / 33

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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.

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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.

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COPS5 bound to COPS5 activates apoptotic process. 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.

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COPS5 inhibits apoptotic process.

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COPS5 inhibits apoptotic process. 10 / 24

| 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].

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COPS5 affects TP53

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COPS5 activates TP53.

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COPS5 activates TP53. 10 / 22

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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.

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COPS5 inhibits TP53.

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COPS5 inhibits TP53. 10 / 17

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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.

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.

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STAT3 affects COPS5

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STAT3 increases the amount of COPS5.

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STAT3 increases the amount of COPS5. 10 / 22

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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.

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Modified STAT3 increases the amount of COPS5. 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.

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STAT3 activates COPS5.

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STAT3 activates COPS5. 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.

21689417

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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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MIF inhibits COPS5. 10 / 15

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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].

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MIF activates COPS5.

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MIF activates COPS5. 6 / 7

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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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COPS5 activates AP1. 10 / 18

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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.

17123647

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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.

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COPS5 inhibits AP1.

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COPS5 inhibits AP1. 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.

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COPS5 affects JUN

1 | 1 15

COPS5 activates JUN.

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COPS5 activates JUN. 10 / 15

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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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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.

| 20

COPS5 activates RAD51.

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COPS5 activates RAD51. 10 / 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.

27524414

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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).

22797071

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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.

22797071

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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).

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COPS5 increases the amount of RAD51.

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COPS5 increases the amount of RAD51. 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.

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Modified COPS5 increases the amount of RAD51. 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.

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COPS5 decreases the amount of RAD51.

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COPS5 decreases the amount of RAD51. 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.

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ERBB2 affects COPS5

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ERBB2 increases the amount of COPS5.

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ERBB2 increases the amount of COPS5. 9 / 12

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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.

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Modified ERBB2 increases the amount of COPS5. 1 / 1

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On the contrary, ectopic expression of HER-2 and neu stimulated Jab1 expression in MCF-7 cells.

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ERBB2 activates COPS5.

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ERBB2 activates COPS5. 4 / 5

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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.

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ERBB2 inhibits COPS5.

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ERBB2 inhibits COPS5. 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.

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COPS5 affects NFkappaB

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COPS5 activates NFkappaB.

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COPS5 activates NFkappaB. 6 / 9

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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.

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COPS5 bound to BCL3 activates NFkappaB. 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].

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COPS5 bound to MIF activates NFkappaB. 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.

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COPS5 inhibits NFkappaB.

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COPS5 inhibits NFkappaB. 6 / 8

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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).

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COPS5 affects cisplatin

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COPS5 activates cisplatin.

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COPS5 activates cisplatin. 10 / 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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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).

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COPS5 inhibits cisplatin.

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COPS5 inhibits cisplatin. 3 / 3

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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.

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COPS5 affects cell cycle

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COPS5 activates cell cycle.

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COPS5 activates cell cycle. 10 / 10

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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.

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COPS5 inhibits cell cycle.

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COPS5 inhibits cell cycle. 5 / 6

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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%.

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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.

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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.

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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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COPS5 affects transcription, DNA-templated

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COPS5 activates transcription, DNA-templated. 10 / 10

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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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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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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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COPS5 bound to JUN activates transcription, DNA-templated. 2 / 2

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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.

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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.

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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.

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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).

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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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Silencing of CSN5 mRNA using siRNA decreased the endogenous protein level of CSN5 and activated L-type Ca (2+) channels expressed in COS7 cells.

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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.

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COPS5 inhibits COPS5.

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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.

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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

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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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COPS5 inhibits HIF1A.

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COPS5 inhibits HIF1A. 1 / 1

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This interaction appears indirect through CSN5 since depletion of CSN5 attenuated the association of exogenous HIF1alpha and MIF, placing CSN5 at the center of the tripartite interaction.

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COPS5 affects Neoplasm Metastasis

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COPS5 activates Neoplasm Metastasis. 10 / 13

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Our previous studies showed that Jab1 / 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 ( 12 ) .

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Additionally, CSN5 contributes to the metastasis and EMT (epithelial-mesenchymal transition) of RCC cells.

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CSN5 promotes the invasion and metastasis of pancreatic cancer by stabilization of FOXM1.

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Previous studies have shown that CSN5 led to the metastasis and EMT activation of cancer cells through decreasing ZEB1 ubiquitination XREF_BIBR.

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Moreover, the anti-metastasis role of CSN5 silence was reversed by MMP2 overexpression, whereas knockdown of MMP2 decreased PC metastasis driven by upregulation of CSN5.

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Taken together, the results indicate that CSN5 can contribute to PC invasion and metastasis through activation of FOXM1 and MMP2 axis.

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Additionally, we found there was a positive correlation between CSN5 and angiopoietin like protein 2 (ANGPTL2) protein levels in thyroid carcinoma tissues and that CSN5 promoted thyroid carcinoma cell proliferation and metastasis through ANGPTL2.

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Additionally , we found there was a positive correlation between CSN5 and angiopoietin-like protein 2 ( ANGPTL2 ) protein levels in thyroid carcinoma tissues and that CSN5 promoted thyroid carcinoma cell proliferation and metastasis through ANGPTL2 .

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Further investigation revealed that CSN5 led to the metastasis and EMT activation of RCC cells through increasing ZEB1 expression.

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TNF affects COPS5

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TNF increases the amount of COPS5.

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TNF increases the amount of COPS5. 9 / 9

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TNF-alpha Upregulates CSN5 Expression to Stabilize PD-L1.

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Proinflammatory cytokine TNFalpha, secreted by M2 macrophages, induces CSN5 expression through IKKbeta and NF-kappaB activation.

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Among the 52 deubiquitinating enzymes identified, CSN5, which possesses enzyme activity in the COP9 signalosome, was robustly expressed in response to TNF-alpha treatment in three cell lines examined (XREF_FIG).

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TNFalpha upregulates CSN5 expression through activation of the transcription factor NF-kappaB p65, which directly transactivates the promoter of the CSN5 encoding gene.

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The results suggested that TNF-alpha upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization.

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Mechanistically, TNF-alpha may activate NF-kappaB and induce CSN5 expression, leading to PD-L1 stabilization.

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It was reported that TNF-α can promote the transcription of CSN5 through activation of the NF-κB signaling pathway.

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NF-κB pathway activated by TNF-α induced CSN5 expression to stabilize PD-L1 expression in cancer cells. xref Palmitoylation of PD-L1 at C272 by DHHC3 blocked mono-ubiquitination of PD-L1 and the subsequent ESCRT-mediated trafficking to multivesicular bodies (MVB), resulting in suppression of PD-L1 lysosomal degradation. xref

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The pro-inflammatory cytokine TNF-α induces the expression of the deubiquitinase CSN5 which deubiquitinates PD-L1 for stabilization (Figure 3), revealing a novel mechanism of immune escape under chronic inflammatory microenvironment [231].

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TNF deubiquitinates COPS5.

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TNF leads to the deubiquitination of COPS5. 2 / 2

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Not only epidermal growth factor (EGF)-mediated glycosylation, which could inactivate GSK3beta, but also COP9 signalosome 5 (CSN5)-mediated deubiquitination induced by TNF-alpha, stabilized PD-L1 expression on tumor cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].

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COPS5 activates TGFB. 4 / 4

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Csn5 and Jab1 can modulate TGF-beta superfamily signaling that is mediated by TGF-beta and BMP through direct interaction with various Smads.

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It is possible that overexpression of Jab1 and CSN5 during the tumorigenic process results in enhanced TGF-beta signaling that contributes to the progression of the disease.

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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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COPS5 bound to SMAD7 activates TGFB. 1 / 1

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Jab1 binds to Smad4, Smad5, and Smad7, key intracellular signaling molecules of the TGF-beta superfamily, and causes ubiquiti nation and/or degradation of these Smads.

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COPS5 bound to SMAD4 activates TGFB. 1 / 1

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Jab1 binds to Smad4, Smad5, and Smad7, key intracellular signaling molecules of the TGF-beta superfamily, and causes ubiquiti nation and/or degradation of these Smads.

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COPS5 bound to SMAD5 activates TGFB. 1 / 1

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Jab1 binds to Smad4, Smad5, and Smad7, key intracellular signaling molecules of the TGF-beta superfamily, and causes ubiquiti nation and/or degradation of these Smads.

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COPS5 inhibits TGFB.

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COPS5 inhibits TGFB. 4 / 5

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Our data suggest that Jab1 antagonizes TGF-beta function by inducing degradation of Smad4 through a distinct degradation pathway.

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Jab1 antagonizes TGF-beta function by inducing uniquitin mediated degradation of Smad4.

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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 antagonizes TGF-beta signaling by inducing Smad4 degradation.

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COPS5 bound to SMAD4 inhibits TGFB. 1 / 1

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29535627

COPS5 affects cell growth

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COPS5 activates cell growth.

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COPS5 activates cell growth. 8 / 10

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JAB1 promoted ESCC cell growth The CCK-8 assay revealed that the Eca109 and EC9706 cells transfected with the JAB1 overexpression lentivirus showed significantly increased absorbance compared to normal cells , ( Fig 3a ) .

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Experiments showing that the knock-down of p8 expression results in a strong inhibition of Jab1 activity confirmed that the mechanism by which Jab1 promotes cell growth by decreasing p27 level is p8 dependent.

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Jab1 and CSN5 promotes NPC cell growth.

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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.

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XREF_BIBR used T83 (a new 4-arylidene curcumin analogue) to inhibit the expression of Jab1 in NPC cells, demonstrating that inhibition of Jab1 could reduce tumor cell growth, induce G 2 / M arrest, and increase tumor cell apoptosis, thus enhancing the sensitivities of NPC cells to radiotherapy.

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Knockdown of COPS5 and COPS6 inhibited cell growth and migration of the CAL27 and SCC25 cell lines.

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In HCC, abnormal expression of JAB1 can significantly reduce CDKN1C and p57 levels and promote tumor cell growth.

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COPS5 inhibits cell growth.

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COPS5 inhibits cell growth. 2 / 2

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Furthermore, restoration of p57 levels induced by loss of Jab1 inhibited tumor cell growth and further increased cell apoptosis in HCC cells.

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CUL4B affects COPS5

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CUL4B inhibits COPS5.

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CUL4B inhibits COPS5. 7 / 7

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Omission of the ubiquitin, E1 and E2, or CUL4B immunocomplexes diminished the Jab1 polyubiquitin ladder.

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Here, accumulation of Jab1 caused by CUL4B knockdown leads to a considerable increase in BMP signaling, which may play a mechanistic role in this process.

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Consistent with the known function of Jab1, the current findings show that the accumulation of Jab1 caused by CUL4B knockdown also leads to a considerable upregulation in BMP signaling.XLID occurrence[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Notably, CUL4B silencing did not cause a change in abundance in the three other homologous mammalian CSN proteins (CSN2, CSN4, and CSN6), indicating the specificity of CUL4B targeted Jab1 degradation.

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CUL4B E3 ligase was shown to mediate the proteasomal degradation of Jab1.

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Here, the experimental evidences showed that CUL4B, but not CUL4A, mediates the proteasomal degradation of Jab1.

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Next, cells treated with siRNAs specific for CUL4B, CUL4B + Jab1 (to offset the effect of Jab1 accumulation caused by silencing of CUL4B), or with control siRNAs.

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CUL4B activates COPS5.

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CUL4B activates COPS5. 3 / 4

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X linked intellectual disability gene CUL4B targets Jab1 and CSN5 for degradation and regulates bone morphogenetic protein signaling.

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As expected, silencing of both CUL4B and Jab1 decreased Jab1 immunofluorescence signals and increased Smad7 signals to levels almost equal to those observed in control RNAi treated cells.

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CUL4B increases the amount of COPS5.

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Modified CUL4B increases the amount of COPS5. 1 / 1

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As shown in Fig. 1 A, lane 3, expression of FLAG-CUL4B could completely rescue the levels of endogenous Jab1.

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COPS5 affects SMAD7

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COPS5 inhibits SMAD7.

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COPS5 inhibits SMAD7. 6 / 6

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Jab1, as a component of Smurf 1/2 E3 ligases, promotes Smad7 degradation [34], serving to negatively regulate BMP signaling by interfering with the phosphorylation of R-Smads [42,43].

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However, Jab1 was also shown to interact with and induce the degradation of Smad7, resulting in increased TGF-beta signaling [XREF_BIBR].

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For example, TIEG and Foxp3 enhance TGF-beta signaling through the repression of Smad7 gene expression, AMSH and AMSH2 interact with inhibitory Smads and suppress their effects, and Jab1 and CSN5 induce Smad7 degradation.

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As expected, silencing of both CUL4B and Jab1 decreased Jab1 immunofluorescence signals and increased Smad7 signals to levels almost equal to those observed in control RNAi treated cells.

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The Smad7 transcriptional regulation is mediated by the Ski protein, which inhibits the Smad7 promoter, and the posttransductional regulation is mediated through the effects of Smurf and Jab1 proteins, which promote Smad7 degradation [XREF_BIBR, XREF_BIBR].

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COPS5 decreases the amount of SMAD7.

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COPS5 decreases the amount of SMAD7. 1 / 3

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Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation

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Modified COPS5 decreases the amount of SMAD7. 1 / 1

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In summary, our results demonstrate that UCHL3 upregulates the levels of SCF beta-TrCP substrates.We have demonstrated that UCHL3 positively regulated COPS5 levels and IFNAR1 levels.

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Modified UCHL3 increases the amount of COPS5. 1 / 1

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Meanwhile, endogenous COPS5 levels were also gradually upregulated by overexpression of increased amounts of UCHL3.

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UCHL3 deubiquitinates COPS5.

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UCHL3 deubiquitinates COPS5. 4 / 4

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Given that UCHL3 interacts with COPS5 in IFN signaling and UCHL3 is a deubiquitinase, we question whether UCHL3 promotes COPS5 deubiquitination.

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To address this question, we firstly performed an in vitro deubiquitination assay, which clearly demonstrated that UCHL3 can deubiquitinate COPS5 in vitro.

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Curcumin inhibits COPS5. 9 / 10

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Curcumin treatment triggered CSN5 degradation, p53 accumulation, and p62 down-regulation concomitantly at 6 h in HCT116 wt and HT29 cells, respectively, but the same CSN5 down-regulation failed to alter p62 in p53-null HCT116 p53-/- cells.

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Second, curcumin inhibits CSN5 associated kinase activity and, therefore, curcumin can inhibit pre-existing CSN5 activity in cancer cells as it can significantly reduce 4T1 tumor growth under natural conditions.

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Curcumin, which has been shown to inhibit CSN5 associated kinase activity, inhibited not only CSN5 activity in a dose dependent manner in vitro (XREF_SUPPLEMENTARY) but also TNF-alpha-induced PD-L1 stabilization in cells from different types of cancers, including breast, colon, and lung cancer, and melanoma (XREF_FIG and XREF_SUPPLEMENTARY).

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Blockade of CSN5 by curcumin destabilized PD-L1 and sensitized cancer to immunotherapy [XREF_BIBR].

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Taken together, we propose that CSN5 down-regulation by curcumin is responsible for giving rise to a rapid p53 protein accumulation without significant activation of intrinsic transcriptional activity of this transcriptional factor, implying a special significance for CSN5 controlled p53 in human cellular response to curcumin.

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In addition, curcumin did not inhibit tumor growth of CSN5 knockout 4T1 cells in mice (XREF_FIG), suggesting that curcumin mediated tumor growth inhibition may be attributed primarily to CSN5 dependent regulation.

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CSN5 associated kinase activity could be inhibited by curcumin, the treatment with which in mice bearing 4T1 tumors slowed tumor growth, increased tumor free survival, and increased IFNgamma+ CD8+ T cells when combined with CTLA-4 blockade.

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We show that curcumin, an important inhibitor of CSN associated kinases, can downregulate not only CSN5 but also MDM2, which results in p53 stabilization.

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Of note, curcumin, but not many other anticancer drugs, induces p53 predominantly by promoting CSN5 degradation [XREF_BIBR, XREF_BIBR].

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Curcumin activates COPS5.

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Curcumin activates COPS5. 1 / 1

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Of note, CSN5 initiated cellular autophagy by curcumin treatment was abolished in p53-null HCT116p 53-/- cancer cells, which could be rescued by reconstitution with wild-type p53 or transcription inactive p53 mutant p53 R273H.

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COPS5 affects proteolysis

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COPS5 inhibits proteolysis.

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COPS5 inhibits proteolysis. 7 / 7

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Jab1 mediates protein degradation of the Rad9-Rad1-Hus1 checkpoint complex.

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Silencing RNA knockdown or overexpression of CSN5 revealed that CSN5 promotes SIAH-1 expression, while CSN5 knockdown also attenuated SIAH-1 protein degradation.

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Jab1 and CSN5 over-expression accelerated the protein degradation of Rad1 and Hus1 significantly, but had a weaker effect on Rad9 and (b)).

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Overexpression of Jab1 accelerated the protein degradation of BRSK2 significantly.

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However, when COPS5 is amplified and overexpressed in endocrine resistant cancer cells, elevated COPS5 and COP9 activity induces global NCoR protein degradation.

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Inversely, overexpression of CSN5 by a Flag-CSN5 fusion construct led to accelerated SIAH-1 protein degradation.

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Therefore, unbalanced activity of Jab1 and CSN5 can directly or indirectly block ubiquitin dependent proteolysis [XREF_BIBR].

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COPS5 activates proteolysis.

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COPS5 activates proteolysis. 2 / 4

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Loss of a CSN subunit, especially CSN5 and CsnE with its catalytic deneddylase activity, leads to mis regulation of CRLs and to a disturbed protein degradation.

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Moreover, the paramyosin accumulations of unc-96 and unc-98 mutants contain CSN-5, a highly conserved component of the COP9 signalosome, which is implicated in regulating ubiquitin mediated proteolysis and is located at A-bands.

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COPS5 affects NCOR

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COPS5 inhibits NCOR.

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COPS5 inhibits NCOR. 9 / 9

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To further evaluate the role of COP9 complex in COPS5 mediated NCoR protein degradation, we examined the role of some COP9 subunits by RNAi.

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However, when COPS5 is amplified and overexpressed in endocrine resistant cancer cells, elevated COPS5 and COP9 activity induces global NCoR protein degradation.

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Low basal level of COP9 and COPS5 is associated with NCoR and constantly degrade and recycle the NCoR complex as part of the repression strategy to prevent coactivator recruitment, similar to the mechanism of cyclical activation XREF_BIBR XREF_BIBR.

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Therefore, tamoxifen retains as an antagonist; (2) in tamoxifen resistant cells, NCoR is globally diminished by degradation due to COPS5 overexpression and consequently high levels of COP9 and COPS5 activity.

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It is also confirmed that overexpression of Jab1 and COPS5 degrades NCoR protein through the ubiquitination-proteasome pathway in breast cancer.

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Satisfyingly, COPS5 reduction and subsequent NCoR upregulation by COPS5 shRNA were observed at the end point of doxycycline and tamoxifen-treatment at day 42 in vivo (XREF_SUPPLEMENTARY, last two lanes).

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COPS5 inhibits MIF. 5 / 5

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This interaction appears indirect through CSN5 since depletion of CSN5 attenuated the association of exogenous HIF1alpha and MIF, placing CSN5 at the center of the tripartite interaction.

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An indirect mechanism between Jab1 and COPS5 and PI3K and AKT pathway has been identified that Jab1 and COPS5 inhibits MIF (autocrine macrophage migration inhibitory factor) secretion and its autocrine pro survival activities and subsequently controls MIF mediated activation of PI3K and AKT signaling.

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Lue et al. [XREF_BIBR] reported that CSN5 functions as a molecular link that retains MIF in the intracellular pools, indicating that CSN5 negatively regulates autocrine MIF activity.

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It appears that a certain optimal cellular JAB1 concentration is needed to facilitate ERK activation by MIF, as a decrease in JAB1 levels, but also JAB1 overexpression, leads to impaired MIF stimulate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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COPS5 affects CTNNB1

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COPS5 increases the amount of CTNNB1.

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COPS5 increases the amount of CTNNB1. 5 / 5

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In this study, we have demonstrated that JAB1 positively regulates the expression of nuclear beta-catenin, c-MYC as a beta-catenin and TCF4 target, and cell cycle regulators, such as Ki-67 and topoisomerase IIalpha, in human CRC cells.

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Together, these experiments indicated that SIAH-1 promotes beta-catenin degradation in HCT116 cells.The data so far suggested that a CSN5 knockdown attenuates beta-catenin levels and Wnt and beta-cate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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We have previously demonstrated that CSN5 knockdown leads to decreased beta-catenin levels in CRC cell lines, thereby diminishing WNT signaling activity [27,28].

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We previously showed that CSN5 and JAB1 increases total beta-catenin levels while it also promotes the short-term proteasomal degradation of beta-catenin in SW480 CRC cells [30].

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Recent studies reveal that Jun activation domain binding protein 1 (JAB1) enhances the degradation of seven in absentia homolog-1 (SIAH-1), a putative E3 ubiquitin ligase of beta-catenin, and positively regulates the expression of total beta-catenin in human CRC cells.

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COPS5 activates CTNNB1.

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COPS5 activates CTNNB1. 4 / 5

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Taken together, these findings suggest that Jab1 promotes glioma cell proliferation and increased expression of Jab1 in glioma patients may amplify beta-catenin signaling to contribute to glioma cell proliferation.

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CSN5 knock-down led to reduced beta-catenin and phospho-bcatenin levels and this was paralleled by reduced CRC cell proliferation and reduced apoptosis rates, whereas the short-term beta-catenin protein stability was enhanced by CSN5 knock-down in SW480 cells.

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Analysis of immunoblots revealed that beta-catenin was downregulated in recipient cells treated with CSN5 knockdown supernatants from donor cells.

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Jab1 promotes glioma cell proliferation by regulating Siah1 and beta-catenin pathway.

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COPS5 inhibits CTNNB1.

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COPS5 inhibits CTNNB1. 1 / 1

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At the same time, we found that CSN5 also promotes the degradation of beta-catenin in SW480 cells, indicating that the effect of CSN5 on beta-catenin levels and associated Wnt signaling could be dicho[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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COPS5 affects SMAD4

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COPS5 inhibits SMAD4.

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COPS5 inhibits SMAD4. 6 / 6

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Importantly, JAB1 has been observed to interact with and induce degradation of SMAD4 [51].

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Jab1 induced Smad4 degradation results in reduced TGF-beta and BMP mediated gene transcription [XREF_BIBR].

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Jab1 can cause degradation of Smad4 via TGF-beta signal pathway, consequently contributing to the proliferation of PC cells.

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We report a novel mechanism of smad4 degradation. Jab1 interacts directly with smad4 and induces its ubiquitylation for degradation

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Examination of the effects of JAB1 induced Smad4 degradation indicates that Jab1 inhibited TGF-beta-induced gene transcription.

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Jab1 and CSN5 induced Smad4 degradation results in reduced TGF-beta-mediated gene transcription, whereas its degradation of Smad7 leads to enhanced TGF-beta signaling effects [XREF_BIBR, XREF_BIBR].

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COPS5 activates SMAD4.

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COPS5 activates SMAD4. 3 / 3

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Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation.

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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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COPS5 inhibits CUL1. 4 / 4

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Since the neddylated : non neddylated Cul1 ratio is higher than normal in csn5 null mutants and lower than normal in Int6 mutants, we reasoned that the csn5 null mutation should rescue the reduced Cul1 neddylation in Int6 mutants.

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Interestingly, we noticed that COPS5 recently was reported to inhibit Cullin1 neddylation (Cope et al., 2002; Muromoto et al., 2013).

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Importantly, JAB1 knockdown induced the activation of SCF ubiquitin ligase complex containing Cullin 1 (CUL1), as judged by the enhancement of covalent modification of CUL1 with the ubiquitin like protein NEDD8, and markedly reduced the basal protein level of IFNR.

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siRNA mediated CSN5 silencing was sufficient to disrupt the CSN complex, and induced Cullin 1 hyperneddylation which was paralleled by a decrease in free NEDD8 (XREF_FIG).

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COPS5-H127A inhibits CUL1. 1 / 1

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In contrast, expression of mutant CSN-5 (H127A, H129A, or D140N) failed to decrease the hyperneddylated Cul1 in the csn-5 KO strain (XREF_FIG).

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COPS5-H129A inhibits CUL1. 1 / 1

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In contrast, expression of mutant CSN-5 (H127A, H129A, or D140N) failed to decrease the hyperneddylated Cul1 in the csn-5 KO strain (XREF_FIG).

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COPS5-D140N inhibits CUL1. 1 / 1

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In contrast, expression of mutant CSN-5 (H127A, H129A, or D140N) failed to decrease the hyperneddylated Cul1 in the csn-5 KO strain (XREF_FIG).

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COPS5 activates CUL1.

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COPS5 activates CUL1. 4 / 4

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The perdurance of the pre-recombinant wild type CSN5 or Nedd8 proteins in post-recombinant mosaic clones for CSN5 or Nedd8 mutations in some cases could allow neurons to successfully execute the Cullin1 mediated earlier program and pass the presumable threshold.

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Subsequently, UCHL3 mediated upregulation of COPS5 promotes Cullin1 deneddylation.

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Here we show that MsrA interacts with Jab1 and consequently, the Jab1 deneddylase activity (removal of Nedd8) is enhanced, causing an increased deneddylation of Cul-1.

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We found these CSN6 mutants compromised their competitive activity in preventing binding between CSN5 and Cullin-1 when compared with wt CSN6; therefore, their capacity to interfere with endogenous CSN5 mediated deneddylation of Cullin-1 was also altered (XREF_FIG).

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COPS5 affects BRSK2

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COPS5 inhibits BRSK2.

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COPS5 inhibits BRSK2. 7 / 7

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Overexpression of Jab1 accelerated the protein degradation of BRSK2 significantly.

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Moreover, exogenous Jab1 reversed BRSK2 mediated G2/M arrest, indicating that BRSK2 is involved in the regulation of cell cycle in mammalian cells.

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The results suggest that Jab1 is able to reverse BRSK2 mediated G2/M phase arrest in mammalian cells.BRSK2 shares high sequence homology with two mice SAD kinases.

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Importantly, treatment with proteasome inhibitor MG132 rescued BRSK2 reduction mediated by Jab1, suggesting that Jab1 induced BRSK2 degradation through proteosome pathway.

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Therefore, it will be meaningful to find out whether Jab1 mediated BRSK2 degradation is associated with oncogenic processes.In conclusion, we present novel findings showing that BRSK2 directly interac[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In an attempt to test whether Jab1 mediates the degradation of BRSK2, we expressed the increasing doses of Jab1 in PANC-1 cells and examined endogenous BRSK2 protein level.

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However, co-expression of Myc-Jab1 decreased HA-BRSK2 immunofluorescent signal and they co-localized in cytoplasm.

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COPS5 decreases the amount of BRSK2.

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Silencing of Jab1 increased BRSK2 protein level in both HEK293T and PANC-1 cells.

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Silencing of endogenous Jab1 increased the cellular BRSK2 protein level.

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COPS5 affects Cyclin_E

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COPS5 activates Cyclin_E.

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COPS5 activates Cyclin_E. 4 / 5

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For example, Doronkin et al. demonstrated that depletion of Jab1 and COPS5 induced cyclin E stability whereas Jab1 and COPS5 overexpression rapidly degraded cyclin E.

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Our results show that the CSN regulates the turnover of Cyclin E. Decreased expression of CSN5 increased Cyclin E stability, and increased CSN5 expression stimulated rapid Cyclin E degradation.

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Also, authors reported that decreased Jab1 and CSN5 expression increased cyclin E stability and that increased Jab1 and CSN5 expression stimulated rapid cyclin E degradation [XREF_BIBR].

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We conclude that CSN5 stimulates Cyclin E degradation.We also overexpressed Cyclin E in wild-type flies to determine its effects on oogenesis when the CSN was not mutant.

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Mutated COPS5 activates Cyclin_E. 1 / 1

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This fact is not surprising because in CSN5 mutants, we found an accumulation of neddylated Cullin1, and a modest reduction in Nedd8 expression in double heterozygotes would be expected to suppress th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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COPS5 inhibits Cyclin_E.

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COPS5 inhibits Cyclin_E. 4 / 4

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We conclude that CSN5 stimulates Cyclin E degradation.We also overexpressed Cyclin E in wild-type flies to determine its effects on oogenesis when the CSN was not mutant.

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These features offer a valuable model for studying the role of cell divisions in cellular differentiation and patterning in a defined lineage.In this paper, we report that CSN5 and CSN mediates SCF de[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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For example, Doronkin et al. demonstrated that depletion of Jab1 and COPS5 induced cyclin E stability whereas Jab1 and COPS5 overexpression rapidly degraded cyclin E.

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Our results show that the CSN regulates the turnover of Cyclin E. Decreased expression of CSN5 increased Cyclin E stability, and increased CSN5 expression stimulated rapid Cyclin E degradation.

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COPS5 affects SIAH1

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COPS5 increases the amount of SIAH1.

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COPS5 increases the amount of SIAH1. 5 / 5

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In this study, we have observed that CSN5 effectively modulated SIAH-1 levels by different mechanisms.

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Silencing RNA knockdown or overexpression of CSN5 revealed that CSN5 promotes SIAH-1 expression, while CSN5 knockdown also attenuated SIAH-1 protein degradation.

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The data in Fig. 4 suggested that CSN5 would enhance SIAH-1 expression.

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This is counter-intuitive at first sight, as it suggested that CSN5 both promotes SIAH-1 expression and degradation.

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COPS5 inhibits SIAH1.

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COPS5 inhibits SIAH1. 2 / 2

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Silencing RNA knockdown or overexpression of CSN5 revealed that CSN5 promotes SIAH-1 expression, while CSN5 knockdown also attenuated SIAH-1 protein degradation.

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Lastly, we demonstrate that CSN5 promotes SIAH-1 degradation in HCT116 and SW480 cells and that this is associated with its deNEDDylase activity.

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COPS5 decreases the amount of SIAH1.

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COPS5 decreases the amount of SIAH1. 1 / 2

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COPS5 activates SIAH1.

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COPS5 activates SIAH1. 1 / 1

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Jab1 promotes glioma cell proliferation by regulating Siah1 and beta-catenin pathway.

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COPS5 affects CD274

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COPS5 increases the amount of CD274.

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COPS5 increases the amount of CD274. 3 / 3

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Indeed, CSN5 inhibition or gene silencing abolished PD-L1 expression and tumor proliferation in vivo.

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Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.

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showed that TNFa signaling resulted in increased expression of COP9 signalosome 5 (CSN5), a deubiquitinating enzyme, to enhance PD-L1 protein expression.

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Half-life analysis using cycloheximide pulse-chase analysis indicated that downregulation of CSN5, but not CSN2, which has been shown to destabilize Snail, reduced PD-L1 expression as well as its protein half-life (XREF_FIG).

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COPS5 activates CD274.

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COPS5 activates CD274. 1 / 1

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Thus, CSN5 inhibits PD-L1 degradation by proteasome complex (Lim et al, 2016).

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S100A7 affects COPS5

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S100A7 activates COPS5. 7 / 8

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Psoriasin (S100A7), a small calcium binding protein that is highly expressed in early breast cancer, enhances Jab1 and CSN5 activity and promotes tumorigenesis [XREF_BIBR, XREF_BIBR].

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Moreover, Psoriasin (S100A7), a small calcium binding protein, enhances Jab1 and COPS5 activity as well as AP-1 activity, and promotes tumorigenesis.

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Overexpression of psoriasin increases nuclear Jab1 and CSN5 activity, resulting in increased AP-1 activity and reduced p27 expression [XREF_BIBR].

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The over expression of psoriasin in MDA-MB-231 breast cancer cells was shown to increase nuclear Jab1 activity and enhance tumorigenesis in vivo in nude mice [XREF_BIBR].

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Mechanistically, S100A7 enhances survival of breast cancer cells by binding to c-Jun activation domain binding protein 1 (Jab1) and increasing activity of NF-kappaB and p-Akt [XREF_BIBR].

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The interaction of S100A7 with Jab1 appears to cause a cellular redistribution of Jab1, resulting in an accumulation in the nucleus [XREF_BIBR].

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We previously observed that expression of S100A7 induces a relative increase in nuclear Jab1 in a breast cell line, and a concurrent reduction in p27 kip1 protein [XREF_BIBR].

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S100A7 bound to JUN activates COPS5. 1 / 1

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Psoriasin interacts with Jun activating binding protein 1 (Jab1), which is involved in multiple signal transduction pathways, including the regulation of c-Jun and AP1 transcription factors XREF_BIBR.

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COPS5 affects cell differentiation

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COPS5 activates cell differentiation.

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COPS5 activates cell differentiation. 6 / 7

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We found that increased expression of JAB1 promoted odontogenic differentiation of DPSCs via Wnt and beta-catenin signaling.

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Interestingly, JAB1 activated CPNE1 related neuronal differentiation.

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Interestingly, JAB1 activated CPNE1 related neuronal differentiation.

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Collectively, our findings suggest that JAB1 activates the neuronal differentiation ability of CPNE1 through the binding of C2A domain in CPNE1 with MPN domain in JAB1.

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JAB1 accelerates odontogenic differentiation of dental pulp stem cells.

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Moreover, the knockdown of Jab1 attenuated 5-HT 6 R agonist induced-Runx2 suppression as well as osteoblast differentiation as evidenced by ALP staining (XREF_FIG) and activity (F) and differentiation markers, ALP, OCN, and bone sialoprotein (BSP) (XREF_FIG).

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COPS5 inhibits cell differentiation.

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COPS5 inhibits cell differentiation. 2 / 2

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In fact, Jab1 -/- nerves show reduced Schwann cell number and increased p27 levels, whereas genetic reduction of p27 in Jab1 -/- mice almost rescues Schwann cell number, differentiation, and the axonal sorting defect.

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Dominant negatives of both JAB-1 and cytohesin-1 inhibited interleukin 2 production and impaired T helper type 1 differentiation.

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COPS5 affects DNA Damage

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COPS5 activates DNA Damage.

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COPS5 activates DNA Damage. 6 / 6

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These results indicate that Jab1 deficiency enhances DNA damage and decreases DNA repair after exposure to DNA damage stimuli.

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On one hand, Cops5 suppresses the autophagic degradation of Mtch2 to direct cellular metabolism toward glycolysis and minimize reactive oxygen species (ROS) production, thereby reducing endogenous DNA damage.

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By building on these findings, we found that Jab1 and CSN5 sensitized mouse embryonic fibroblasts to gamma radiation induced apoptosis and increased spontaneous DNA damage that could be attributed to reduced levels of the DNA repair protein Rad51 and increased levels of p53 [XREF_BIBR].

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These results indicated that Jab1 and CSN5 deficiency enhances DNA damage and decreases DNA repair in NPC cells after exposure to DNA damaging stimuli.

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Similarly, the levels of phospho- Chk2, a key molecule in the transduction of DNA damage signals [XREF_BIBR], increased in NPC cells after DNA damage exposure regardless of whether the cells were treated with Jab1 and CSN5 siRNA (although the phospho-Chk2 levels were higher in Jab1 and CSN5 deficient cells).

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COPS5 inhibits DNA Damage.

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COPS5 inhibits DNA Damage. 3 / 3

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Previous investigation by our group showed that Jab1 deletion sensitized both primary embryonic fibroblasts and osteosarcoma cells to gamma-radiation-induced apoptosis and increased spontaneous DNA damage and homologous recombination defects 43.

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

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COPS5 affects Cell Survival

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COPS5 activates Cell Survival.

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COPS5 activates Cell Survival. 5 / 6

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Jab1 mediated cell viability changes after UV and treatment with HU is tightly correlated with the lowered level of the 9-1-1 complex in cells).

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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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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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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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COPS5 decreases the amount of STAT3.

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COPS5 decreases the amount of STAT3. 2 / 2

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Although JAB1 knockdown tended to increase nuclear STAT3 expression, it significantly decreased unphosphorylated STAT3 DNA binding activity.

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Doxycycline inhibits CSN5 activity in vitro.

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In this in vitro system, doxycycline inhibited CSN5 catalyzed deneddylation with an IC 50 about 110 muM.

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Thus, doxycycline selectively inhibits CSN5, instead of being a general inhibitor of the JAMM family, likely through a mechanism more than mere zinc chelation.

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The fact that doxycycline inhibited CSN5 activity significantly in vitro only at relatively high drug concentrations (IC 50 : ~ 110 muM) thus raised the question whether the concentrations of doxycycline in the DLBCL cells under our experimental conditions were sufficient to inhibit CSN5 activity.

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Collectively, the results support the idea that doxycycline inhibits CSN5 function in cultured DLBCL cells.

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To investigate whether doxycycline indeed inhibits the activity of CSN5 in DLBCL cells, we examined the effect of doxycycline treatment on cullin neddylation.

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Doxycycline accumulates in DLBCL cells and inhibits CSN5 function in these cells.

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Doxycycline treatment resulted in an increase in the neddylated (slower migrating) forms of Cullin-1 and Cullin-2 in the DLBCL cells, indicating that doxycycline inhibits CSN5 activity in DLBCL cells.

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COPS5 affects calcium(2+)

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COPS5 inhibits calcium(2+). 8 / 8

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In rat, CSN5 inhibits cardiac L-type Ca 2+ channel activity through protein protein interactions.

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Inhibition of CSN5 expression by siRNA enhanced the L-type Ca 2+ currents.

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Thus, the possible mechanisms by which CSN5 inhibits L-type Ca channels might be through an inhibition of the expression of the α subunit at the cell surface membrane and/or a reduction of availabilit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Because endogenous CSN5 expressed in COS7 cells may interact with and regulate the expressed Ca 2+ channels, we next examined effects of the inhibition of endogenous CSN5 on the Ca 2+ currents.Inhibit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Thus, the possible mechanisms by which CSN5 inhibits L-type Ca 2+ channels might be through an inhibition of the expression of the alpha 1C subunit at the cell surface membrane and/or a reduction of a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The result suggests that endogenous CSN5 expressed in COS7 cells interacts with recombinant cardiac L-type Ca 2+ channel and that the endogenous protein level of CSN5 in these cells is sufficient to i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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These data indicate that inhibition of endogenous CSN5 in COS7 cells enhances the activity of recombinant L-type Ca 2+ channels.Inhibition of CSN5 expression had no effect on the kinetics of L-type Ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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COPS5 affects Radiation, Ionizing

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COPS5 activates Radiation, Ionizing. 8 / 8

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Our study revealed that Jab1 depletion contributes to increased UV and IR and cisplatin sensitivity by increasing DNA damage and suppressing DNA repair, which in turn, contributes to an increase in cisplatin-, IR-, and UV induced apoptosis.

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Consistent with impaired HR function in Jab1 knockdown cells, we also found that Jab1 +/- MEFs, compared with wild-type MEFs, significantly increased cell death in response to death stimuli UV IR and gamma-IR (XREF_FIG).

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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 comparison, the levels of expression of Ku70, known to be an important protein in the NHEJ DNA-repair pathway, and of phospho-Chk2, a key molecule in the transduction of DNA damage signaling induced by DSBs [XREF_BIBR, XREF_BIBR], were increased after IR exposure regardless of whether the cells were treated with Jab1 and CSN5 or control siRNA.

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These observations suggested that Jab1 and CSN5 is a major contributor to the resistance of NPC to UV radiation, IR, and cisplatin.

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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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RELA affects COPS5

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RELA activates COPS5.

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RELA activates COPS5. 7 / 7

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Conversely, COP9 signalosome 5 (CSN5), induced by nuclear factor kappaB p65, is required for tumor necrosis factor-alpha (TNF-alpha)-mediated PD-L1 stabilization in cancer cells either by direct deubiquitination or by inhibiting ubiquitination and degradation of PD-L1 (XREF_FIG).

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In addition, p65 stimulated CSN5 activation, whereas a dominant negative IkappaBalpha mutant (IkappaBalpha 2SA) abolished p65 induced COPS5 promoter activation (XREF_FIG).

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We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-kappaB p65, is required for TNF-alpha-mediated PD-L1 stabilization in cancer cells.

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P65, but not its heterodimeric partner p50, stimulated CSN5 activation through the p65 binding site, and mutation of the binding site on the COPS5 promoter abrogated p65 mediated COPS5 promoter activity (XREF_FIG).

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Transcriptional Activation of CSN5 by p65 Is Required for TNF-α-Mediated PD-L1 Stabilization.

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Transcriptional Activation of CSN5 by p65 Is Required for TNF-α-Mediated PD-L1 Stabilization.

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Transcriptional Activation of CSN5 by p65 Is Required for TNF-alpha-Mediated PD-L1 Stabilization.

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RELA increases the amount of COPS5.

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RELA increases the amount of COPS5. 1 / 1

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Together with the positive correlation between p65 and CSN5 found in the Cancer Cell Line Encyclopedia (XREF_SUPPLEMENTARY), these results suggested that TNF-alpha-activated p65 transcriptionally upregulates CSN5 expression, which is required for TNF-alpha-mediated PD-L1 stabilization and related functions.

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COPS5 affects Neoplasm Invasiveness

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COPS5 activates Neoplasm Invasiveness.

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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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Taken together, the results indicate that CSN5 can contribute to PC invasion and metastasis through activation of FOXM1 and MMP2 axis.

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Strikingly, the knockdown of COPS5 significantly decreased both the migratory ability and invasiveness of both A549 and Panc-1 cell lines, in concert with the reduction of SNAIL and its downstream target protein, Vimentin [XREF_BIBR].

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CSN5 promotes the invasion and metastasis of pancreatic cancer by stabilization of FOXM1.

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Using an in vitro invasion assay, we found that knockdown of either Stat3 or Jab1 significantly decreased NPC cell invasion (XREF_FIG).

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Further, silencing of CSN5 expression markedly inhibited PC invasion and metastasis in vitro and in vivo, accompanied by decreased MMP2 expression.

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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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COPS5 inhibits Neoplasm Invasiveness.

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COPS5 inhibits Neoplasm Invasiveness. 1 / 1

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As shown in Figure XREF_FIG, their invasiveness were significantly suppressed by knocking-down of COPS5 in both H1650 and H2228 in concert with SNAIL reduction, suggesting the important role of COPS5 in the invasiveness of lung cancers independent of their specific oncogenic mutations.

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COPS5 affects NEDD8

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COPS5 inhibits NEDD8.

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COPS5 inhibits NEDD8. 4 / 4

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In particular, CSN inhibition of CRL4 DDB2 is non enzymatic, independent of CSN5 mediated cleavage of ubiquitin like protein Nedd8, whose conjugation to Cullins activates Cullin based ubiquitin ligase.

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Indeed, conditional silencing of CSN5 in HEK293 cells increased the neddylation of cullins.

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Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed " deNEDDylase ") and a subunit of the cullin RING E3 ligase regulating COP9 signalosome complex, attenuates proinflammatory NF-kappaB signaling.

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CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits.

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COPS5 activates NEDD8.

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COPS5 activates NEDD8. 4 / 4

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Knockdown of the CSN subunit 5 (CSN5) and suppression of CSN mediated removal of Nedd8 (deneddylation) reduce FBP levels in human cells [10,11] indicating that a major function of the CSN is the prote[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The Jab1 and MPN domain metalloenzyme (JAMM) motif in the Jab1 and Csn5 subunit was found to underlie CSN 's Nedd8 isopeptidase activity.

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NEDD8 cleavage by CSN is catalysed by CSN5, a Zn (2+)-dependent isopeptidase that is inactive in isolation.

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The Csn5 subunit in S. pombe and D. melanogaster underlies the Nedd8 isopeptidase activity of the CSN XREF_BIBR.

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COPS5 affects Ubiquitin

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COPS5 inhibits Ubiquitin.

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COPS5 inhibits Ubiquitin. 3 / 4

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While Csn5 is thought to impede the action of ubiquitin ligases through shaving cullins from their Rub1 and Nedd8 modification (and possibly also by deubiquitinating substrates bound to the cullins), the outcome of Rpn11 inhibition will depend largely on whether Rpn11 participates primarily in shaving substrates from their chains, promoting release and rescue, or in trimming the polyubiquitin tag, allowing for proteolysis quality control (XREF_FIG).

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Indeed , ectopic expression of IFIT3 in U937 human myeloid cells resulted in the sequestration of JUN activation domain-binding protein 1 ( JAB1 ; also known as COPS5 ) , which limited ubiquitin - and proteasome-dependent degradation of cyclin-dependent kinase inhibitor 1B ( also known as p27 and KIP1 ) .

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Mechanistic studies showed that Jab1 induced ubiquitin independent proteasomal p14ARF degradation in gastric cancer cells.

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COPS5 bound to MIF inhibits Ubiquitin. 1 / 1

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Hence, MIF interacts with Jab1 and CSN5 and negatively regulates the cullin-1-containing ubiquitin E3 ligase complex with effects on p27- and E2F1-3-dependent cell cycle control [XREF_BIBR, XREF_BIBR].

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COPS5 activates Ubiquitin.

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COPS5 activates Ubiquitin. 2 / 2

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Independently, IFIT proteins may modulate expression of negative regulators of the cell cycle, resulting in the accumulation of cells at the G 1 / S phase transition 60; ectopic expression of IFIT3 in U937 human myeloid cells resulted in sequestration of c-Jun activation domain binding protein-1 (JAB1), which limited ubiquitin and proteasome dependent degradation of cyclin dependent kinase inhibitor 1B (also known as p27 or KIP1).

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Given parasites including E. histolytica express cullins and Nedd8 proteins XREF_BIBR - XREF_BIBR, it is plausible that JAB1 in parasites regulate cullins by deneddylation and modulate ubiquitin proteasomal system (UPS) activity, however, further studies to confirm this are needed.

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COPS5 decreases the amount of Ubiquitin.

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COPS5 decreases the amount of Ubiquitin. 1 / 1

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COPS5 affects MYC

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COPS5 activates MYC.

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COPS5 activates MYC. 2 / 3

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However, a protein called CSN5 (also known as Jab1) that had been previously shown to posttranscriptionally promote MYC activation in breast epithelium [XREF_BIBR] was found to be overexpressed in early HCC in parallel with induction of the MYC regulated gene expression signature.

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Interestingly, it has been reported that JAB1 knockdown stabilized MYC protein level, but inhibited MYC induced transcriptional activity [37], suggesting that JAB1 increased the turnover of MYC protei[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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COPS5 increases the amount of MYC.

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COPS5 increases the amount of MYC. 2 / 2

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COPS5 decreases the amount of MYC.

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COPS5 decreases the amount of MYC. 1 / 1

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COPS5 decreases the amount of MYC. 1 / 1

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Moreover, knockdown of CSN2 or CSN5 did not upregulate c-Myc protein expression in NIH3T3 cells (Figs.

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COPS5 inhibits MYC.

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COPS5 inhibits MYC. 1 / 1

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In contrast, CSN5 knockdown led to accumulation of the neddylated form of Cullin-1 and destabilization of Fbxw7, causing accumulation of Myc (XREF_FIG).

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COPS5 affects cell death

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COPS5 inhibits cell death.

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COPS5 inhibits cell death. 4 / 4

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However, the molecular mechanisms by which loss of JAB1 leads to cell death are still unclear.

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Deletion of both Jab1 alleles caused embryonic lethality and accelerated cell death in blastocysts, indicating the essential role of Jab1 during mouse development.

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CSN5 knockdown caused mitotic defects, G2/M arrest and apoptotic cell death.

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COPS5 activates cell death.

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COPS5 activates cell death. 3 / 3

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

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In both, Bezielle inhibited cell proliferation, induced cell death and G2 cycle arrest by regulating the mediator proteins Jab1, p27 (Kip1) and p21 (Cip1).

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COPS5 affects SOX9

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COPS5 activates SOX9.

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COPS5 activates SOX9. 4 / 4

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Moreover, in Jab1 knockout mutants, Sox9 expression and activity was severely compromised, suggesting Jab1 positively regulates Sox9 in early growth plate development.

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Notably, Jab1 by itself did not activate Sox9 reporter in 10T1/2 cells (XREF_FIG).

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COPS5 activates JNK. 3 / 4

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In addition, MIF interaction with Jab-1 leads to the inhibition of JNK signaling pathways, which are otherwise activated by unbound Jab-1.

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NRBP1 regulates the apoptotic pathway by inhibiting Jab1-mediated JNK signaling, which is essential in gene translation and regulation of cellular apoptosis (70–72); it may thus play a key role in suppressing CRC tumorigenesis.

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MIF inhibits JAB1 and CSN5 mediated AP-1 activity and reduces JNK activity stimulated by JAB1 and CSN5.

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COPS5 activates JNK. 1 / 1

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COPS5 inhibits JNK.

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COPS5 inhibits JNK. 2 / 2

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MIF signals through at least three cell surface receptors, including the CD74/44 complex, CXCR2 and CXCR4 16-18 but also signals by intracellular interaction with the JAB-1 thus inhibiting JNK activation and p27 Kip1 -dependent cell-cycle regulation.

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COPS5 affects ERN1

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COPS5 inhibits ERN1.

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COPS5 inhibits ERN1. 2 / 4

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Tumor formation experiments in vitro showed that the tumor size, microvessel density and VEGF expression of CRC cells with high expression of Dkk1 decreased, and that CSN5, miR-410 and HotTip could promote the progress of CRC by inhibiting the expression of Dkk1.

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Here, we show that CSN5 suppresses DKK1 expression and secretion in CRC cells, thereby promoting WNT signaling.

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Interestingly, CSN5 knockdown increased intracellular DKK1 protein levels in SW480 cells.

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COPS5 inhibits CDKN2A.

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COPS5 inhibits CDKN2A. 3 / 3

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Ubiquitination assay was performed to validate whether ubiquitination is involved in Jab1 mediated p14ARF degradation.

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Furthermore , Jab1 decreased the expression of p14ARF though ubiquitination independent proteasomal degradation .

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Then , we investigated the mechanism that how Jab1 induced p14ARF depletion .

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COPS5 decreases the amount of CDKN2A.

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COPS5 decreases the amount of CDKN2A. 3 / 3

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Jab1 promotes gastric cancer tumorigenesis via non-ubiquitin proteasomal degradation of p14ARF.

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Expression of the tumor suppressor p16 (INK4a) was inversely correlated with that of JAB1, and the oncoprotein SMYD3, a newly identified JAB1 interactor, suppressed transcription of p16 in cooperation with JAB1.

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Furthermore, Jab1 decreased the expression of p14ARF though ubiquitination independent proteasomal degradation.

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COPS5 activates CDKN2A.

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COPS5 activates CDKN2A. 1 / 1

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Then, we investigated the mechanism that how Jab1 induced p14ARF depletion.

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COPS5 affects localization

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COPS5 activates localization.

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COPS5 activates localization. 5 / 5

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Jab1 and CSN5 induces the cytoplasmic localization and degradation of RUNX3.

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

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Jun activation domain binding protein 1 (Jab and CSN5) induces the cytoplasmic localization and degradation of RUNX3 [XREF_BIBR].

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COPS5 activates Proteasome. 3 / 3

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Indeed, ectopic expression of IFIT3 in U937 human myeloid cells resulted in the sequestration of JUN activation domain-binding protein 1 (JAB1; also known as COPS5), which limited ubiquitin- and proteasome-dependent degradation of cyclin-dependent kinase inhibitor 1B (also known as p27 and KIP1).

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Down-regulation of human CSN4 or CSN5 induced proteasome mediated degradation of the ubiquitin conjugating enzyme UBC3 and Cdc34.

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SRC affects COPS5

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SRC increases the amount of COPS5. 2 / 5

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Taken together, it is evident that both IL-6 and Src signaling through Stat3 is contributing to Jab1 transcription and increased expression in breast cancer.

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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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COPS5 affects cellular senescence

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COPS5 activates cellular senescence. 5 / 5

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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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Further studies revealed that depletion of Jab1 inhibited 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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It will be promising to explore small molecules which inhibit interaction between Jab1 and CDK2 but do n't affect the deneddylase activity of Jab1, which may induce senescence without affecting global proliferation and the cell cycle, resulting in the development of anti-cancer drugs with minimum side effects.

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Depletion of CSN5 induces senescence in p53-null fibroblasts XREF_BIBR, but knockout of the CSN5 gene upregulates p53 expression XREF_BIBR, indicating that CSN5 occurs upstream of both p53 dependent and -independent senescence pathways (XREF_FIG) and that interaction between CSN5 and CDK2 may take part in the p53 independent pathway.

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COPS5 affects CREB3

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In the case of Luman, this regulatory mechanism does not seem plausible, since JAB1 repression of Luman was also observed in the GAL4 reporter system, in which Luman was recruited to the artificial GA[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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We found that JAB1 could repress the activation potential of Luman and decrease its protein stability.The Matchmaker 3 yeast two-hybrid system and a pre-transformed adult human brain Matchmaker cDNA l[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Here we show that, in a similar manner, JAB1 might also downregulate the transactivation activity of Luman during the UPR.

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JAB1 and CSN5 inhibits the activity of Luman and CREB3 by promoting its degradation.

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COPS5 affects CPNE1

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COPS5 activates CPNE1. 5 / 5

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Collectively, our findings suggest that JAB1 activates the neuronal differentiation ability of CPNE1 through the binding of C2A domain in CPNE1 with MPN domain in JAB1.

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Interestingly, JAB1 activated CPNE1 related neuronal differentiation.

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Defining the interaction modules on both proteins will be important to further characterize the mechanism of CPNE1 mediated cell differentiation by JAB1.

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It is interesting point to find about detail mechanism of JAB1 up-regulation of CPNE1 function.Generally, the function of the MPN domain has been related to ubiquitin isopeptidase and deubiquitinase i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Nevertheless, it is not clear about the mechanism of JAB1 up-regulation of CPNE1 function.

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Troglitazone affects COPS5

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Troglitazone decreases the amount of COPS5.

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Animal studies verified that intratumor or i.p. injection of troglitazone attenuated HCC growth and reduced Jab1 expression in tumor tissues.

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Animal studies confirmed that troglitazone inhibited hepatocellular carcinima cell growth and decreased Jab1 and COPS5 expression in tumor tissues.

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Troglitazone inhibits COPS5.

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Another potential target drug is troglitazone which suppress Jab1 and COPS5 promoter activity by inhibiting Sp1- and Tcf4 mediated Jab1 transcription.

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NFkappaB affects COPS5

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NFkappaB increases the amount of COPS5.

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NFkappaB increases the amount of COPS5. 3 / 3

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COPS5 increases the amount of TXN. 3 / 3

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Reconciling this paradox, we show here that Csn5 catalysed cullin (Cul) deneddylation and Ubp12 mediated deubiquitination cooperate in maintaining the stability of labile substrate adapters, thus facilitating CRL function.

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In turn, the protected Jab1 activity can prevent the degradation of Cullin RING E3 ligases by the Ub/Ub like dependent degradation pathways.

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These observations present a paradox : If CSN5 causes Cullin deneddylation via its metalloprotease activity, why does CSN promote CRL activity?

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Thus, both a 2-hour MLN treatment and a long-term CSN5 siRNA knockdown attenuate the degradation of SIAH-1, while a 2-hour MLN treatment applied to CSN5 siRNA-knockdown cells does not further add to t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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COPS5 inhibits CUL.

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COPS5 inhibits CUL. 1 / 1

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Here, we examined whether repression of CSN5 expression (and thereby inhibition of CULLIN deneddylation) might influence ADORA2B dependent stabilization of PER2.

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COPS5 affects SNAIL

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COPS5 activates SNAIL.

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COPS5 activates SNAIL. 3 / 3

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COPS5 directly regulates SNAIL stability through deubiquitination.

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Although the potential involvement of Smad7 in COPS5 dependent metastasis regulation still needs to be determined, we observed the sustained SNAIL mRNA expression (data not shown) even after COPS5 knock-down, supporting the post-translational SNAIL regulation by COPS5.

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COPS5 increases the amount of RANBP9. 1 / 2

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COPS5 (Jab1) protein increases beta site processing of amyloid precursor protein and amyloid beta peptide generation by stabilizing RanBP9 protein levels.

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Modified COPS5 increases the amount of RANBP9. 2 / 2

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Interestingly, COPS5 overexpression increased RanBP9 levels in the brain, which, in turn, led to increased amyloidogenic processing of APP, as reflected by increased levels of sAPPbeta and decreased levels of sAPPalpha.

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Finally, COPS5 levels were increased significantly in AD brains and APDeltaE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life.

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COPS5 activates RANBP9.

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COPS5 activates RANBP9. 1 / 1

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Furthermore, like RanBP9, COPS5 robustly increased Abeta generation, followed by increased soluble APP-beta (sAPP-beta) and decreased soluble-APP-alpha (sAPP-alpha) levels.

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Most importantly, down-regulation of COPS5 by siRNAs reduced Abeta generation, implying that endogenous COPS5 regulates Abeta generation.

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COPS5 activates APP.

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COPS5 activates APP. 2 / 2

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Taken together, these results suggest that COPS5 increases Abeta generation by increasing RanBP9 levels.

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Furthermore, like RanBP9, COPS5 robustly increased Abeta generation, followed by increased soluble APP-beta (sAPP-beta) and decreased soluble-APP-alpha (sAPP-alpha) levels.

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COPS5 decreases the amount of APP.

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Modified COPS5 decreases the amount of APP. 1 / 1

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COPS5 affects JUN_family

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COPS5 activates JUN_family. 3 / 4

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MIF binds to JUN-activation domain-binding protein 1 (JAB1), preventing JAB1-induced activation of JUN and JAB1-induced degradation of the cell-proliferation inhibitor KIP1, thereby leading to cell-cycle arrest and apoptosis.

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SP1 decreases the amount of COPS5. 3 / 3

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LPA increases the amount of COPS5. 2 / 2

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In the current study, we showed that LPA stimulated the interaction of CSN5 with exogenously expressed MIF-2xFLAG and HA-HIF1alpha (XREF_FIG).

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Nonetheless, we observed that LPA enhanced the expression of MIF and CSN5 in the nucleus.

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LPA activates COPS5.

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LPA activates COPS5. 2 / 2

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COPS5 inhibits unc-98. 3 / 3

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Knockdown of csn-5 results in an increase in the level of UNC-98 protein and a slight reduction in the level of UNC-96 protein, suggesting that normally CSN-5 promotes the degradation of UNC-98 and stabilizes UNC-96.

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In the double knockdown of csn-5 and -6, the levels of UNC-98 protein were increased and the levels of UNC-96 protein levels were slightly reduced, suggesting that CSN-5 promotes the degradation of UNC-98 and that CSN-5 stabilizes UNC-96.

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COPS5 activates unc-98.

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COPS5 activates unc-98. 1 / 1

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RNAi knockdown of CSN-5 results in an increase in UNC-98 protein, suggesting that the function of CSN-5 is to promote the degradation of UNC-98.

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COPS5 affects CDKN

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COPS5 activates CDKN.

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COPS5 activates CDKN. 3 / 3

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

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COPS5 inhibits CRL. 2 / 2

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CSN is regulated by auto-inhibition, which is only released upon binding of NEDDylated CRL to ensure that CSN5 specifically inhibits the active NEDDylated CRLs [127] .

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COPS5 inhibits AKT. 2 / 2

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In addition, CSN5 silencing may induce activation PI3K and AKT signal regulated cell invasion.

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COPS5 affects CUL3

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COPS5 inhibits CUL3. 3 / 3

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Nevertheless, the csn5 null mutation did not rescue the reduced Cul3 neddylation caused by the lack of Int6 since Cul3 neddylation in the Int6 173-1 -csn5 null double homozygous larvae is very similar to that of the Int6 173-1 single mutant (XREF_FIG, compare lanes 5 and 6).

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However, by the time the cells initiate this phase, the cytoplasmic CSN5 or Nedd8 proteins could be already used up, preventing the successful execution of the Cullin3 dependent program.

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Western blot analysis demonstrated that Jab1 deletion increased the abundance of neddylated CUL3.

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COPS5 affects BRR2

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COPS5 activates BRR2. 3 / 3

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The Jab1 and MPN domain of Prp8 increases the unwinding activity of Brr2 invitro.

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It has been shown that the Jab1 and MPN domain enhances the unwinding activity of Brr2.

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One possible mechanism how the Jab1 and MPN domain activates Brr2 could be releasing the brake imposed by the HLH domain.

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BBR affects COPS5

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BBR inhibits COPS5. 3 / 3

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In the present study, we found BBR specific binds to and inhibits the activity of CSN5, leading to ubiquitination and subsequent degradation of PD-L1.

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To further confirm BBR directly binds to and inactivates CSN5, a molecular docking model of BBR with crystal structure of CSN5 (PDB ID : 5JOG) was established.

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Our findings show that BBR inhibited CSN5 activity and reduced PD-L1-based immunosuppression.

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PI3K affects COPS5

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PI3K inhibits COPS5.

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PI3K inhibits COPS5. 2 / 2

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Besides, PI3K and Akt may participate in the regulation of Jab1 and COPS5 by Bcr-Abl since PI3K and Akt inhibitor LY294002 decreases the promoter activity and mRNA level of Jab1 and COPS5.

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We explored a potential connection between PI3K activity and Jab1 and E2F1 target gene induction, and found that E2F1 and Jab1 co-induction of apoptotic target genes can be inhibited by activated PI3K.

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PI3K decreases the amount of COPS5.

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PI3K decreases the amount of COPS5. 1 / 1

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COPS5 activates cell adhesion. 1 / 2

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Furthermore, knockdown of CSN5 significantly inhibited cell adhesion and reduced the number of invasive cells, while increasing the percentage of cells in the G0/G1 phase (P < 0.05).

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COPS5 inhibits cell adhesion.

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COPS5 inhibits cell adhesion. 1 / 1

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COPS5 affects RUNX2

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COPS5 inhibits RUNX2.

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COPS5 inhibits RUNX2. 2 / 2

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COPS5 activates E3_Ub_ligase. 2 / 2

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CSN5 and Jab1 deconjugates the Ub like modifier Nedd8 to modulate the activity of the SCF E3 ligase [XREF_BIBR].

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In turn, the protected Jab1 activity can prevent the degradation of Cullin RING E3 ligases by the Ub/Ub like dependent degradation pathways.

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COPS5 inhibits E3_Ub_ligase.

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COPS5 bound to MIF inhibits E3_Ub_ligase. 1 / 1

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COPS5 affects DDB2

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COPS5 activates DDB2.

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COPS5 activates DDB2. 2 / 2

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CEBPB increases the amount of COPS5. 1 / 2

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IGF-I, which is a well-known AKT activator, also up-regulated the expression of Jab1 in NIH/3T3 and MCF-7 cells.

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EGF affects COPS5

COPS5 activates RUNX3. 2 / 2

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Subsequently, JAB1 knockdown significantly decreased the expression levels of MDR1, NANOG, and VEGF, which are STAT3 target genes.

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UCHL5 increases the amount of COPS5. 1 / 1

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

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UCHL5 decreases the amount of COPS5.

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Modified UCHL5 decreases the amount of COPS5. 1 / 1

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

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UCHL1 affects COPS5

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UCHL1 deubiquitinates COPS5.

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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

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UCHL1 activates COPS5.

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UCHL1 activates COPS5. 1 / 1

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Interestingly, UCH-L1 has been observed to interact with Jab1, a regulator of p27 Kip1, suggesting that UCH-L1 may modulate Jab1 in a manner that leads to increased p27 Kip1 degradation and potentiate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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RPN13 affects COPS5

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RPN13 increases the amount of COPS5.

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Modified RPN13 increases the amount of COPS5. 1 / 1

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10 Overexpression of Rpn13 or Rpn1 upregulated the COPS5 protein levels and downregulated the p53 protein levels.

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RPN13 deubiquitinates COPS5.

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RPN13 leads to the deubiquitination of COPS5. 1 / 1

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In conclusion, our results showed that treatment of b-AP15 rescued the protein level of p53 and blocked its nuclear export and ubiquitination degradation induced in UPP by Rpn13- and Rpn1 mediated and UCH37 dependent COPS5 deubiquitylation.

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NEDD8 affects COPS5

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NEDD8 activates mutated COPS5. 1 / 1

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NEDD8 activates COPS5. 1 / 1

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The presence of NEDD8 is required to activate the CSN5 active site.

IFNG increases the amount of COPS5. 1 / 1

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In contrast, IFN-gamma did not induce CSN5 expression.

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IFNG activates COPS5.

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IFNG activates COPS5. 1 / 1

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COPS8 increases the amount of COPS5. 1 / 1

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The decrease in CSN8 suppressed protein levels of CSN3, CSN5 and CSN7 but had little effect on CSN1, CSN2, CSN4, and CSN6 protein levels (XREF_FIG).

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COPS8 activates COPS5.

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COPS8 activates COPS5. 1 / 1

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Consistently, CSN8 knockdown reduced the abundance of CSN8 and CSN5 in both holo- and mini-complexes.

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COPS5 affects signal transduction

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COPS5 bound to KMT2D activates signal transduction. 1 / 1

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Intracellular human short form ALR (sfALR) binds to Jun Activation domain Binding protein 1 (JAB-1) and potentiates Activator Protein-1 (AP-1) signalling pathway in a sulfhydryl oxidase dependent manner XREF_BIBR.

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COPS5 bound to JUN activates signal transduction. 1 / 1

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COPS5 inhibits Wnt. 1 / 1

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It is suggested that CSN5 may actively drive abnormal Wnt signals by inhibiting Wnt antagonist Dkk1, thus promoting the development of colorectal cancer.

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COPS5 activates Wnt.

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COPS5 activates Wnt. 1 / 1

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COPS5 inhibits TIMELESS. 1 / 1

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CSN4 and CSN5 are required for light mediated TIM degradation in larval LNs.

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COPS5 activates TIMELESS.

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COPS5 activates TIMELESS. 1 / 1

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These effects are cell autonomous because restoration of CSN5 expression only to larval LNs rescued the defects in TIM degradation (XREF_FIG), whereas expression of a dominant negative CSN5 transgene specifically in larval LNs blocked TIM degradation as effectively as null mutations in CSN4 and CSN5 (XREF_FIG).

COPS5 inhibits KITLG. 1 / 1

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COPS5 activates KITLG.

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COPS5 activates KITLG. 1 / 1

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CSN5 and Jab1 deconjugates the Ub like modifier Nedd8 to modulate the activity of the SCF E3 ligase [XREF_BIBR].

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COPS5 affects IL2

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COPS5 increases the amount of IL2.

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Catalytically active COPS5 increases the amount of IL2. 1 / 1

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Modified assertion

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COPS5 activates IL2.

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COPS5 activates IL2. 1 / 1

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Dominant negatives of both JAB-1 and cytohesin-1 inhibited interleukin 2 production and impaired T helper type 1 differentiation.

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COPS5 affects FBXW7

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COPS5 increases the amount of FBXW7.

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COPS5 increases the amount of FBXW7. 1 / 1

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Treatment of Csn5 depleted cells with the proteasome inhibitor MG132 largely restored normal levels of Fbx7, cyclin F, and Fbw7, whereas Skp2 levels were only partially rescued.

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COPS5 activates FBXW7.

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COPS5 activates FBXW7. 1 / 1

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These results suggest that an increase in degradation rate of ET A R after long-term ET-1 stimulation is mediated by an increase in the amount of Jab1 bound to ET A R.It is reported that in the absenc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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COPS5 bound to MFSD11 activates EDN1. 1 / 1

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Shikonin affects COPS5

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Shikonin increases the amount of COPS5. 1 / 1

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Shikonin blocked immune evasion in PC, and lowered the expression of PD-L1, NF-kappaB, NF-kappaB p65, STAT3 and CSN5 invivo and invitro.

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STAT1 affects COPS5

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Radiation, Ionizing affects COPS5

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Radiation, Ionizing increases the amount of COPS5. 1 / 1

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Jab1 Expression is Induced by IR, and Silencing Jab1 Replicates the Effects of miR-24 Under IR, Whereas Exogenous Expression of Jab1 without its 3 ' UTR and 5 ' UTR can Rescue the Inhibition Effect by miR-24.

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RFX1 affects COPS5

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RFX1 decreases the amount of COPS5. 1 / 1

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No evidence text available

RECK affects COPS5

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RECK increases the amount of COPS5. 1 / 1

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RECK inhibited the erbB signaling and attenuated the expression of the downstream molecules Jun activation domain binding protein 1 (JAB1) and the DNA repair protein RAD51 to impede DNA repair and to increase drug sensitivity.

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