COPS6 Data Analysis

HGNC Gene Name
COP9 signalosome subunit 6
HGNC Gene Symbol
COPS6
Identifiers
hgnc:21749 NCBIGene:10980 uniprot:Q7L5N1
Orthologs
mgi:1349439 rgd:1309919
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for COPS6
Number of Papers
47 retrieved on 2022-05-22

DepMap Analysis

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

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

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type
RAN RAN, member RAS oncogene family 0.357 0.20 1.04 3.07e-04
PMPCB peptidase, mitochondrial processing subunit beta 0.343 0.03 0.10 6.41e-01
BUB3 BUB3 mitotic checkpoint protein 0.335 -0.31 -1.80 1.05e-08
HSPE1 heat shock protein family E (Hsp10) member 1 0.329 -0.39 -2.25 8.00e-14
OR2A25 olfactory receptor family 2 subfamily A member 25 0.325
SRRT serrate, RNA effector molecule 0.312 -0.17 -1.02 3.45e-03
RNPC3 RNA binding region (RNP1, RRM) containing 3 0.299 -0.32 -1.85 3.52e-09

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with COPS6using 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

Literature Mining

INDRA was used to automatically assemble known mechanisms related to COPS6 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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COPS6 leads to the deubiquitination of TRIM21. 2 / 2
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Moreover, MLN4924 treatment abrogated TRIM21 ubiquitination promoted by CSN6.

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45 Interestingly, CSN6 is able to decrease the steady-state expression of TRIM21 by enhancing TRIM21 ubiquitination, thereby promoting cancer stemness.
COPS6 leads to the deubiquitination of POU2F1. 2 / 2
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Moreover, overexpression of CSN6 reduced OCT1 ubiquitination, while ectopic expression of TRIM21 reversed this effect.

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Simultaneously, knockdown of CSN6 increased OCT1 ubiquitination, while knockdown of TRIM21 reversed this impact.
COPS6 leads to the deubiquitination of CDK9. 2 / 2
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In addition, to investigate whether CSN6 controls the ubiquitination and degradation of the E3 ligase UBR5 to stabilize CDK9, in vivo ubiquitination assays were performed and found that CSN6 increased UBR5 ubiquitination levels and decreased CDK9 ubiquitination levels in melanoma cells and 293FT cells.

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CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5 mediated ubiquitination and degradation of CDK9.
COPS6 leads to the deubiquitination of MDM2 on K364. 2 / 2
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Mechanism studies indicated that CSN6 prevented MDM2 autoubiquitination at lysine 364, resulting in stabilization of MDM2 and degradation of p53.

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Previous studies have demonstrated that CSN6 prevents MDM2 autoubiquitination at lysine 364, which results in the stabilization of MDM2 and the degradation of p53.
Modified COPS6 leads to the deubiquitination of JUN. 1 / 1
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In addition, overexpression of CSN6 could also reduce the ubiquitination of the proto-oncoprotein c-Jun mediated by the E3 ubiquitin ligase MEKK1 and promote cell proliferation in the human embryonic kidney cell lines XREF_BIBR.
Modified COPS6 leads to the deubiquitination of MYC. 1 / 1
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Because Myc is degraded through the ubiquitin pathway 38, we examined whether ubiquitination is involved and found that CSN6 overexpression inhibited Myc ubiquitination while shRNA-CSN6 increased Myc ubiquitination (XREF_FIG).
COPS6 leads to the deubiquitination of mutated EGFR. 1 / 1
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Reduction of mutant EGFR ubiquitination by CSN6 causes steadily elevated levels of EGFR, leading to proliferation, migration, invasion, and tumorigenesis 35.
Modified COPS6 leads to the deubiquitination of MDM2 on K364. 1 / 1
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Expression of CSN6 appeared to prevent MDM2 autoubiquitination at lysine 364, resulting in stabilization of MDM2 and degradation of p53.
COPS6 leads to the deubiquitination of E6. 1 / 1
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Meanwhile, CSN6 could bind to the E6 oncoprotein of human papillomavirus (HPV) and inhibit the polyubiquitination of E6 to reduce its degradation, thereby regulating the activity of p53 in cell proliferation and apoptosis to affect the development of cervical cancer XREF_BIBR.

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
COPS6 affects CTNNB1
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COPS6 increases the amount of CTNNB1.
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COPS6 increases the amount of CTNNB1. 7 / 8
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In line with this finding, western blotting revealed that knockdown of CSN6 by shRNA decreased the expression of beta-catenin and increased the expression of beta-Trcp.

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CSN6 positively regulates beta-catenin expression in a beta-Trcp-dependent manner and triggers the expression of several EMT related genes regulated by beta-catenin.

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CSN6 positively regulated beta-catenin expression in a beta-Trcp-dependent manner and triggered expression of several EMT related genes regulated by beta-catenin.

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CSN6 positively regulates beta-catenin expression.

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CSN6 increased the steady-state expression of beta-catenin in a dose dependent manner while downregulating beta-Trcp.

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Together, the results suggest that CSN6 may positively regulate beta-catenin transcription, thereby mediating the EMT.

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CSN6 increased the steady-state expression of beta-catenin in a dose dependent manner while downregulating beta-Trcp (XREF_FIG).
Modified COPS6 increases the amount of CTNNB1. 3 / 3
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Furthermore, continuous knockdown of CSN6 expression in K1 and PTC cells decreased the beta-catenin protein levels, whereas the restoration of beta-catenin expression using an expression vector (Cat-pcDNA, Cat) increased expression of both vimentin mRNA and protein to some extent.

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Overexpression of CSN6 could increase the expression of beta-catenin target genes (XREF_SUPPLEMENTARY).

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Overexpression of CSN6 could increase the expression of beta-catenin target genes.
COPS6 activates CTNNB1.
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COPS6 activates CTNNB1. 9 / 9
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The TOP-FLASH TCF/LEF -1 luciferase reporter gene analyses showed that Flag-CSN6 significantly increased beta-catenin transactivation, but the activity of Flag-CSN6-S148A was compromised.

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Furthermore, we demonstrate that CSN6 enhances beta-catenin stability and that the CSN6 associated protein beta-Trcp negatively regulates beta-catenin stability.

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Because KRAS is an upstream regulator of these two pathways, KRAS mutations will continue to activate both RAS-MAPK and AKT pathways to stabilize CSN6, which in turn activates beta-catenin activity to cause pathogenesis in colon cancer.

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CSN6 Positively Regulates beta-Catenin Protein Stability and Facilitates the Transcriptional Activity of beta-Catenin.

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Given that CSN6 positively regulates beta-catenin by regulating beta-Trcp ubiquitination, 41 CSN6 may also regulate ALDH1A1 expression through the beta-catenin pathway.

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The TOP-FLASH TCF/LEF -1 luciferase reporter gene analyses showed that Flag-CSN6 significantly increased beta-catenin transactivation but the activity of Flag-CSN6-S148A was compromised (XREF_FIG).

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Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt and beta-catenin signaling and sensitizes cancer cells to FH535 therapy.

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CSN6 positively regulates beta-catenin protein stability and facilities the EMT in PTC cells.

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Here, we provided another example of CSN6 preserved Cullin neddylation in affecting another F-box protein -- beta-Trcp and showed how CSN6 can destabilize beta-Trcp and subsequently increase the stability of beta-catenin.
COPS6 inhibits CTNNB1.
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COPS6 inhibits CTNNB1. 6 / 6
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The CSN6 knockdown mediated beta-catenin destabilization translated into beta-catenin 's reduced transcriptional activity, as evidenced by qRT-PCR findings showing diminished expression of beta-cateni[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Furthermore, we demonstrate that CSN6 enhances beta-catenin stability and that the CSN6 associated protein beta-Trcp negatively regulates beta-catenin stability.

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As expected, we found that the beta-catenin level decreased and that of beta-Trcp increased when cells were treated with CSN6-shRNA (CSN6 knockdown) (Fig XREF_FIG A and B).

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The CSN6 knockdown mediated beta-catenin destabilization translated into beta-catenin 's reduced transcriptional activity, as evidenced by qRT-PCR findings showing diminished expression of beta-catenin target genes, including myc, cyclin D, and vascular endothelial growth factor (XREF_FIG).

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CSN6 overexpression reduced the turnover rate of beta-catenin and increased the turnover rate of beta-Trcp.

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CSN6 overexpression reduced the turnover rate of beta-catenin and increased the turnover rate of beta-Trcp (XREF_FIG).
COPS6 decreases the amount of CTNNB1.
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COPS6 decreases the amount of CTNNB1. 3 / 3
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Furthermore, CSN6 increased the ubiquitination level of beta-Trcp and reduced the ubiquitination level of beta-catenin (XREF_FIG).

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Furthermore, CSN6 increased the ubiquitination level of beta-Trcp and reduced the ubiquitination level of beta-catenin.

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Congruently, CSN6 knockdown xenograft tumors had elevated beta-Trcp and diminished beta-catenin expression and a slower growth rate.

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In vitro and in vivo data showed that loss of CSN6 attenuated cell proliferation, migration, and invasion of PTC cells, confirming the vital function of CSN6 in PTC.

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COP9 signalosome subunit 6 mediates PDGF -induced pulmonary arterial smooth muscle cells proliferation.

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Thus, loss of CSN6 expression inhibits PTC proliferation and migration.

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CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo.

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To investigate the cell viability of CSN6-knockdown melanoma cells, a 3-[4, -5-dimethylthiazol-2-yl]-2, -5-diphenyltetrazolium bromide (MTT) assay was conducted and revealed that CSN6 knockdown remarkably inhibited melanoma cell proliferation in vitro.

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Overexpression of CSN6 promoted processes of HCC cell proliferation, migration, and invasion, while these processes were inhibited when CSN6 was silenced.

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Furthermore, in CSN6-knockdown melanoma cells, UBR5 knockdown abrogated the effects caused by CSN6 silencing, suggesting that CSN6 activates the UBR5 and CDK9 pathway to promote melanoma cell proliferation and metastasis.

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This study revealed that CSN6 knockdown in melanoma cells inhibited cell proliferation in vitro and tumorigenicity in mice by inducing cell cycle arrest and that the anti-proliferative effect could be rescued by overexpressing CSN6 in CSN6-knockdown melanoma cells, suggesting that CSN6 has critical roles in triggering melanoma initiation and progression.

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MTT and BrdU assays revealed that recovery of CSN6 expression rescued cell growth and proliferation.

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Second, functional assays showed that CSN6 inhibition significantly reduced both the motility and the proliferation of PTC cells.

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In addition, overexpression of CSN6 could also reduce the ubiquitination of the proto-oncoprotein c-Jun mediated by the E3 ubiquitin ligase MEKK1 and promote cell proliferation in the human embryonic kidney cell lines XREF_BIBR.

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Because 14-3-3sigma suppresses CSN6 mediated cell proliferation and anchorage independent growth, we next examined the impact of 14-3-3sigma on CSN6 mediated tumor promotion.

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In summary, these findings demonstrated that downregulation of CSN6 expression could inhibit cell proliferation, migration and invasion.
COPS6 affects MYC
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COPS6 activates MYC.
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COPS6 activates MYC. 8 / 9
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We have shown that CSN6 increases Myc stability.

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CSN6 increase Myc stability by reducing Myc ubiquitination.

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Furthermore, Fbxw7 deficiency compromised CSN6 shRNA enhanced Myc ubiquitination (XREF_FIG), suggesting that CSN6 mediated Myc stabilization is dependent on Fbxw7.

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While CSN6 expression increased Myc transcriptional activity, CSN6 knockdown by shRNA reduced Myc transcriptional activity (XREF_FIG).

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CSN6 mediated Myc stabilization translated to increased Myc transcriptional activity, as evidenced by increasing Myc luciferase reporter gene activity (XREF_FIG) and qRT-PCR for expression of Myc target genes, including CdC25A, Adm-1, and Odc-1 (XREF_FIG).

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Noticeably, reduced expression of Csn6 in Emicro-Myc background can also contribute to p53 stabilization in 33% of Emicro-Myc and Csn6 +/- lymphomas when compared with Emicro-Myc and Csn6 +/+, suggesting that both CSN6 mediated p53 downregulation and CSN6 mediated Myc elevation contribute to lymphomagenesis of this system (XREF_FIG).

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Thus our study has provided a novel mechanistic answer to how CSN6 can destabilize Fbxw7 and subsequently increase the stability of Myc.

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Accordingly, CSN6 mediated Myc increases occurred only in HCT116 Fbxw7 +/+ cells (XREF_FIG).
COPS6 inhibits MYC.
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COPS6 inhibits MYC. 3 / 3
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Knockdown of CSN6 decreased the steady-state expression of Myc protein in HCT116 Fbxw7 +/+ but not in HCT116 Fbxw7 -/- cells (XREF_FIG).

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Compared with empty vector transfected control cells, cells transfected with CSN6 had a decelerated endogenous Myc turnover rate (XREF_FIG); the pulse chase analyses of over expressed Myc with CSN6 or with shRNA mediated CSN6 knockdown indicated that over expression of CSN6 stabilized Myc while shRNA-CSN6 increased Myc degradation (XREF_FIG).

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While CSN6 expression increased Myc transcriptional activity, CSN6 knockdown by shRNA reduced Myc transcriptional activity (XREF_FIG).
COPS6 increases the amount of MYC.
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Modified COPS6 increases the amount of MYC. 2 / 2
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Overexpression of CSN6 reduced the protein levels of Fbxw7alpha and increased Myc protein levels; while CSN6 knockdown by shRNA resulted in increased protein levels of Fbxw7alpha and decreased protein levels of Myc in two cell lines HCT116 and U2OS cells (XREF_FIG).

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Overexpression of CSN6 increased the mRNA levels of Myc transcriptional targets (CDC25A, cyclin D1, and Tert) and decreased the mRNA levels of Myc transcriptionally repressed genes (p27Kip1, CDKN2B, and p21Cip1), while loss of CSN6 reversed the expression of these Myc target genes.
COPS6 increases the amount of MYC. 1 / 1
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Compared with wt CSN6, which clearly decreased Fbxw7 expression and increased Myc expression in U2OS cells, the MPN-KQV CSN6 mutant lost these functions (XREF_SUPPLEMENTARY).
COPS6 decreases the amount of MYC.
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Modified COPS6 decreases the amount of MYC. 2 / 2
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Overexpression of CSN6 reduced the protein levels of Fbxw7alpha and increased Myc protein levels; while CSN6 knockdown by shRNA resulted in increased protein levels of Fbxw7alpha and decreased protein levels of Myc in two cell lines HCT116 and U2OS cells (XREF_FIG).

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Overexpression of CSN6 increased the mRNA levels of Myc transcriptional targets (CDC25A, cyclin D1, and Tert) and decreased the mRNA levels of Myc transcriptionally repressed genes (p27Kip1, CDKN2B, and p21Cip1), while loss of CSN6 reversed the expression of these Myc target genes.
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CSN6 recovery rescued the cell proliferation, migration, and invasion of CSN6-knockdown melanoma cells.

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Here, we report that GBM tumors overexpressed CSN6 compared with normal brain tissues and that CSN6 promoted GBM cell proliferation, migration, invasion and tumorigenesis.

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Here, we identified that CSN6 promoted melanoma cell migration and invasion in vivo.

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In this study, we show that CSN6 promotes the growth, migration and invasion of melanoma cells via CDK9 mediated signaling pathways.

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In melanoma cells , CSN6 knockdown remarkably inhibited cell proliferation , tumorigenicity , migration , and invasion , whereas CSN6 recovery rescued the proliferative and metastatic abilities .

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Here , we identified that CSN6 promoted melanoma cell migration and invasion in vivo .

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Also, WT CSN6 increased cell migration and invasion in a wound healing assay (p < 0.001, XREF_FIG) and in transwell migration and invasion assays (XREF_FIG), whereas CSN6 S148A lost such capability, demonstrating that the CSN6 promoted migration and invasion of colon cancer cells requires a phosphorylation event.

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CSN6 Promotes the Migration and Invasion of Cervical Cancer Cells by Inhibiting Autophagic Degradation of Cathepsin L.

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In vitro and in vivo data showed that loss of CSN6 attenuated cell proliferation, migration, and invasion of PTC cells, confirming the vital function of CSN6 in PTC.

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These results suggest that CSN6 robustly modulates PTC migration and invasiveness.

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In summary, these findings demonstrated that downregulation of CSN6 expression could inhibit cell proliferation, migration and invasion.
COPS6 affects fbxw1
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COPS6 activates fbxw1.
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COPS6 activates fbxw1. 5 / 5
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CSN6 overexpression reduced the turnover rate of beta-catenin and increased the turnover rate of beta-Trcp (XREF_FIG).

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Western blotting revealed that the CSN6 mediated beta-Trcp downregulation in K1 cells could be rescued by the proteasome inhibitor MG132.

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CSN6 overexpression reduced the turnover rate of beta-catenin and increased the turnover rate of beta-Trcp.

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qRT-PCR analysis revealed that the mRNA levels of beta-Trcp and beta-catenin were not affected by CSN6 overexpression, and western blotting revealed that CSN6 mediated beta-Trcp downregulation could b[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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qRT-PCR analysis revealed that the mRNA levels of beta-Trcp and beta-catenin were not affected by CSN6 overexpression (XREF_SUPPLEMENTARY), and western blotting revealed that CSN6 mediated beta-Trcp downregulation could be rescued by the proteasome inhibitor MG132 (XREF_FIG).
COPS6 inhibits fbxw1.
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COPS6 inhibits fbxw1. 4 / 4
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Because Cullin neddylation, a process controlled by CSN, decreases the steady-state expression levels of F-box proteins (Wee et al., 2005), we rationalized that CSN6 may be involved in Cullin neddylat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Because Cullin neddylation, a process controlled by CSN, decreases the steady-state expression levels of F-box proteins, we rationalized that CSN6 may be involved in Cullin neddylation, thereby increasing the autocatalytic degradation of beta-Trcp.

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As expected, we found that the beta-catenin level decreased and that of beta-Trcp increased when cells were treated with CSN6-shRNA (CSN6 knockdown) (Fig XREF_FIG A and B).

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In the xenografted colon cancer samples, CSN6 depletion inhibited tumor growth by increasing beta-Trcp while downregulating beta-catenin.
COPS6 decreases the amount of fbxw1.
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COPS6 decreases the amount of fbxw1. 2 / 2
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Thus, we explored whether CSN6 negatively regulated beta-Trcp expression to stabilize beta-catenin in PTC cells.

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In line with this finding, western blotting revealed that knockdown of CSN6 by shRNA decreased the expression of beta-catenin and increased the expression of beta-Trcp.
Modified COPS6 decreases the amount of fbxw1. 1 / 1
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Strikingly, our studies showed that CSN6 expression decreases the steady-state expression of beta-Trcp.
COPS6 increases the amount of fbxw1.
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COPS6 increases the amount of fbxw1. 2 / 2
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Furthermore, CSN6 increased the ubiquitination level of beta-Trcp and reduced the ubiquitination level of beta-catenin.

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Furthermore, CSN6 increased the ubiquitination level of beta-Trcp and reduced the ubiquitination level of beta-catenin (XREF_FIG).
EGF affects COPS6
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EGF increases the amount of COPS6.
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EGF increases the amount of COPS6. 5 / 5
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Immunoblot analysis showed that EGF treatment increased the steady-state expression of CSN6 in DLD-1 colon cancer cells, whereas inhibition of MEK and ERK by the MEK1 inhibitor PD98059 diminished the EGF induced increase of CSN6 expression (XREF_FIG).

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Treatment with calf intestinal alkaline phosphatase (CIP) reduced the EGF induced steady-state expression of CSN6, indicating that CSN6 phosphorylation is required in this process and presumably acts [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Immunoblot analysis showed that EGF treatment increased the steady-state expression of CSN6 in DLD-1 colon cancer cells, whereas inhibition of MEK and ERK by the MEK1 inhibitor PD98059 diminished the [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Furthermore, we found that EGF treatment increased the S60 phosphorylation level of CSN6 with concurrent Akt phosphorylation.

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Treatment with calf intestinal alkaline phosphatase (CIP) reduced the EGF induced steady-state expression of CSN6, indicating that CSN6 phosphorylation is required in this process (XREF_FIG) and presumably acts through ERK.
EGF decreases the amount of COPS6.
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EGF decreases the amount of COPS6. 4 / 4
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We assessed the ubiquitination of CSN6 in the presence of EGF and found that EGF reduced the ubiquitination level of WT CSN6 but not that of the CSN6 S148A mutant.

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We assessed the ubiquitination of CSN6 in the presence of EGF and found that EGF reduced the ubiquitination level of WT CSN6 but not that of the CSN6 S148A mutant (XREF_FIG).

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Furthermore, we found that EGF treatment or ERK2 activation decreases the ubiquitination level of CSN6 (XREF_FIG).

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Furthermore, we found that EGF treatment or ERK2 activation decreases the ubiquitination level of CSN6.
EGF inhibits COPS6.
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EGF inhibits COPS6. 2 / 2
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Congruently, PD98059 increased the turnover rate of CSN6 in the presence of the de novo protein synthesis inhibitor cycloheximide (XREF_FIG), whereas EGF, which induced ERK activation, reduced CSN6 turnover (XREF_FIG).

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Congruently, PD98059 increased the turnover rate of CSN6 in the presence of the de novo protein synthesis inhibitor cycloheximide, whereas EGF, which induced ERK activation, reduced CSN6 turnover.
EGF deubiquitinates COPS6.
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EGF leads to the deubiquitination of COPS6. 1 / 1
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Together, these results indicate that EGF and ERK mediated CSN6 phosphorylation and diminished CSN6 ubiquitination and turnover.
EGF activates COPS6.
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EGF activates COPS6. 1 / 1
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The CSN6 S148A mutant did not respond to EGF induced upregulation, whereas the WT CSN6 was upregulated by EGF.
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CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9 As a critical subunit of the constitutive photomorphogenesis 9 ( COP9 ) signalosome ( CSN ) , CSN6 is upregulated in some human cancers and plays critical roles in tumorigenesis and progression , but its biological functions and molecular mechanisms in melanoma remain unknown .

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CSN6 inhibition suppresses pancreatic adenocarcinoma metastasis via destabilizing the c-Fos protein.

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Our study reveals that CSN6 promotes the migration and metastasis of breast cancer cells, indicating that CSN6 functions as an oncogene in breast cancer cells.

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Moreover, we demonstrated that CSN6 promoted invasion and metastasis through regulating forkhead box protein A1 (FOXA1) in PAAD cells.

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CSN6 promotes tumor metastasis via up-regulating snail1 in xenograft model.

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Re-expression of FOXA1 rescued the decreased invasion and metastasis caused by CSN6 knockdown, whereas inhibition of FOXA1 alleviated the pro metastasis effect induced by CSN6 overexpression.

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CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9 .

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The results demonstrated that CSN6 promoted tumor metastasis in vivo and up-regulated the protein level of Snail1 , which was consistent with the results mentioned in vitro experiments .

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CSN6 has the capability to promote the formation of spheres enriched in CSCs, suggesting that CSN6 overexpression may promote distant metastasis and confer resistance after chemotherapy.

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CSN6 promotes tumor metastasis via up-regulating snail1 in xenograft model To identify the role of CSN6 in the metastatic potency of breast cancer cells in vivo , lentiviruses packed with CSN6-NC or CSN6 overexpression vectors were transfected into MDA-MB-231 cell lines , and the fluorescence intensity was detected by Olympus light microscope ( Figure 4A ) .
AKT affects COPS6
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AKT activates COPS6.
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AKT activates COPS6. 5 / 6
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For instance, Akt can positively regulate CSN6 by phosphorylation.

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We previously showed that S60 of CSN6 has an Akt phosphorylation site [XREF_BIBR] and that Akt increases the steady-state expression of CSN6 [XREF_BIBR], which in turn will be translating into E6AP stabilization.

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Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6.

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Our mechanistic studies showed that EGF and Akt mediated CSN6 S60 phosphorylation and subse quent stabilization of E6AP thereby causing p53 downregulation and promoting cell proliferation, cell transformation as well as tumorigenesis.

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Hence, this study has further strengthened the significance of the MDM2-p53 pathway on tumorigenesis through a novel link of Akt mediated CSN6 activation.
AKT increases the amount of COPS6.
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AKT increases the amount of COPS6. 2 / 2
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We previously showed that S60 of CSN6 has an Akt phosphorylation site (Xue et al., 2012) and that Akt increases the steady-state expression of CSN6 (Xue et al., 2012).

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We previously showed that S60 of CSN6 has an Akt phosphorylation site and that Akt increases the steady-state expression of CSN6.
Modified AKT increases the amount of COPS6. 1 / 1
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Ectopic expression of Akt can increase the expression of CSN6; accordingly, Akt inhibition leads to CSN6 destabilization.
COPS6 affects UBR5
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COPS6 inhibits UBR5.
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COPS6 inhibits UBR5. 4 / 4
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Next , western blot analysis demonstrated that CSN6 increased CDK9 expression and decreased UBR5 expression in a dose-dependent manner in 293FT cells ( Fig. 5B ) .

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In addition, our study described a novel CSN6 interacting E3 ligase UBR5, which was negatively regulated by CSN6 and could regulate the ubiquitination and degradation of CDK9 in melanoma cells.

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This study demonstrated that UBR5, a novel E3 ubiquitin ligase interacting with CSN6, was negatively regulated by CSN6 and was responsible for CDK9 ubiquitination and degradation in melanoma cells.

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Indeed, we revealed that CSN6 reduces the stability of UBR5 by regulating the ubiquitin mediated degradation of UBR5, furtherly stabilizing CDK9 expression, suggesting that UBR5 may be a downstream factor of CSN6 in melanoma cells.
COPS6 decreases the amount of UBR5.
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COPS6 decreases the amount of UBR5. 2 / 2
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Furthermore, we found that UBR5 knockdown rescued all the effects induced by CSN6 silencing, indicating that CSN6 activates the CDK9 pathway to promote melanoma growth and metastasis by reducing the UBR5 level.

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Next, western blot analysis demonstrated that CSN6 increased CDK9 expression and decreased UBR5 expression in a dose dependent manner in 293FT cells.
COPS6 activates UBR5.
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COPS6 activates UBR5. 2 / 2
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Furthermore, in CSN6-knockdown melanoma cells, UBR5 knockdown abrogated the effects caused by CSN6 silencing, suggesting that CSN6 activates the UBR5 and CDK9 pathway to promote melanoma cell proliferation and metastasis.

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Then, western blot analysis showed that the proteasome inhibitor MG132 could rescue CSN6 mediated UBR5 downregulation.
COPS6 increases the amount of UBR5.
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COPS6 increases the amount of UBR5. 1 / 1
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In addition, to investigate whether CSN6 controls the ubiquitination and degradation of the E3 ligase UBR5 to stabilize CDK9, in vivo ubiquitination assays were performed and found that CSN6 increased UBR5 ubiquitination levels and decreased CDK9 ubiquitination levels in melanoma cells and 293FT cells.
COPS6 affects AKT
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COPS6 activates AKT. 7 / 8
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Our mechanistic studies of CSN6 mediated 14-3-3sigma downregulation explains how CSN6 can activate Akt in our proposed model (XREF_FIG).

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Our mechanistic studies of CSN6-mediated 14-3-3σ downregulation explains how CSN6 can activate Akt in our proposed model ( xref ).

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The observation that CSN6 increases the activity of Akt (XREF_FIG) is very intriguing.

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Consistent with this, we found that CSN6 can downregulate the expression of 14-3-3sigma and lead to Akt activation.

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Because 14-3-3sigma suppresses Akt activity, we first examined whether knockdown of CSN6 could suppress Akt activity and inhibit Akt mediated cell survival.

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In addition to demonstrating amplification of the CSN6 gene locus at 7q22.1 in human mammary tumors, xref they report that AKT phosphorylation at Ser60 stabilizes CSN6. xref Interestingly, by promoting 14–3-3σ degradation through stabilization of its E3-ligase COP1, CSN6 can activate AKT to create a self-propelling positive feedback loop xref ( xref ).

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XREF_BIBR Interestingly, by promoting 14-3-3sigma degradation through stabilization of its E3-ligase COP1, CSN6 can activate AKT to create a self propelling positive feedback loop XREF_BIBR (XREF_FIG).
COPS6 affects CUL1
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COPS6 activates CUL1. 7 / 7
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35 Interestingly, CSN6 can increase CUL1 neddylation.

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We then found that increasing amounts of CSN6 enhanced neddylation of wild type Cullin-1 but not the Cullin-1 mutant 41 in which the Nedd-8-conjugating site lysine (K) 720 was mutated to arginine (R) (XREF_SUPPLEMENTARY).

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CSN6 knockdown reduced the neddylated form of Cullin-1, leading to accumulation of Fbxw7, which in turn caused downregulation of Myc (XREF_FIG).

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We further showed that overexpression of dominant negative Ubc12 (dnUbc12-HA) XREF_BIBR, XREF_BIBR, which antagonized CSN6 mediated increase of Cullin-1 neddylation, compromised CSN6 mediated Fbxw7alpha downregulation (XREF_FIG).

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On the other hand, mono-allelic deletion of CSN6 decreases Cullin1 neddylation, stabilizes FBXW7, and compromises lymphomagenesis in an Emu-Myc mouse model [XREF_BIBR].

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Together, these data suggest that CSN6 increases Cullin-1 neddylation by competing with CSN5 for binding to Cullin-1 through the MPN domain, thereby facilitating Cullin-1-enhanced Fbxw7 degradation.

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CSN6 enhanced neddylation of Cullin-1 and facilitated auto-ubiquitination and degradation of Fbxw7, a component of CRL involved in Myc ubiquitination, thereby stabilizing Myc.
COPS6 activates mutated CUL1. 1 / 1
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We then found that increasing amounts of CSN6 enhanced neddylation of wild type Cullin-1 but not the Cullin-1 mutant 41 in which the Nedd-8-conjugating site lysine (K) 720 was mutated to arginine (R) (XREF_SUPPLEMENTARY).
| 1 6
| 1 6

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These results indicate that CSN6 affects the EMT process of cancer cells by up-regulating the expression of Snail1 protein and promotes cell migration .

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Furthermore, migration and invasion assays showed that knockdown of CSN6 reduced cell migration and invasion in DLD-1.

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CSN6 promotes the cell migration of breast cancer cells by positively regulating Snail1 stability.

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Also, WT CSN6 increased cell migration and invasion in a wound healing assay (p < 0.001, Figure 3 I) and in Transwell migration and invasion assays, whereas CSN6 S148A lost such capability, demonstrat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Here, we identified that CSN6 promoted melanoma cell migration and invasion in vivo.

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CSN6 promoted the cell migration and wound healing abilities in breast cancer cell lines.

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Also, WT CSN6 increased cell migration and invasion in a wound healing assay (p < 0.001, XREF_FIG) and in transwell migration and invasion assays (XREF_FIG), whereas CSN6 S148A lost such capability, demonstrating that the CSN6 promoted migration and invasion of colon cancer cells requires a phosphorylation event.
COPS6 affects TP53
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COPS6 inhibits TP53.
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COPS6 inhibits TP53. 5 / 5
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Moreover, CSN6 promotes p53 degradation through a mechanism that stabilizes MDM2 protein by limiting its auto-ubiquitylation.

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Moreover, CSN6 could n't induce p53 degradation in Mdm2-null mouse embryonic fibroblasts, suggesting that CSN6 mediated degradation of p53 is MDM2 dependent.

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These results suggest that loss of CSN6 enhances p53 mediated tumor suppression in vivo and that CSN6 plays an important role in regulating DNA damage associated apoptosis and tumorigenesis through control of the MDM2-p53 signaling pathway.

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Through combinatorial effects on the MDM2-p53 signaling axis and now SKP2 mediated p57 Kip2 degradation, it is hypothesized that CSN6 overexpression can effectively promote cell proliferation by simultaneously relieving cell cycle restraints, apoptosis, senescence, and presumably p53 functions in DNA damage repair and cell metabolism, among other important tumor suppressive mechanisms.

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Similarly, it was found that over-expression of CSN6 can promote p53 degradation through inhibiting autoubiquitylation of MDM2, and mice that were heterozygous for CSN6 were more susceptible to DNA damage [XREF_BIBR].
COPS6 activates TP53.
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COPS6 activates TP53. 2 / 2
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Noticeably, reduced expression of Csn6 in Emicro-Myc background can also contribute to p53 stabilization in 33% of Emicro-Myc and Csn6 +/- lymphomas when compared with Emicro-Myc and Csn6 +/+, suggesting that both CSN6 mediated p53 downregulation and CSN6 mediated Myc elevation contribute to lymphomagenesis of this system (XREF_FIG).

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Since 14-3-3sigma is regulated by p53, at issue is whether CSN6 mediated 14-3-3sigma downregulation involves p53.
COPS6 affects COPS6
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COPS6 activates COPS6.
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COPS6 activates COPS6. 5 / 5
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CSN6 mRNA levels did not increase significantly in response to EGF (XREF_SUPPLEMENTARY), suggesting that EGF regulates CSN6 posttranslationally.

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CSN6 mRNA levels did not increase significantly in response to EGF, suggesting that EGF regulates CSN6 posttranslationally.

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The EGF-ERK2 Axis Phosphorylates CSN6 on S148 and Enhances CSN6 Stabilization.

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In addition, phosphorylation of CSN6 increases the stability of CSN6, thereby promoting its regulatory capacity.

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CSN6 S60 phosphorylation is known to increase the stability of CSN6 [XREF_BIBR].
COPS6 inhibits COPS6.
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COPS6 inhibits COPS6. 2 / 2
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Mechanistic studies revealed that CSN6 is deregulated by epidermal growth factor receptor (EGFR) signaling, in which ERK2 binds directly to CSN6 Leu163 and Val165 and phosphorylates CSN6 at Ser148.

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Mechanistic studies revealed that CSN6 is deregulated by EGFR signaling, in which ERK2 binds directly to CSN6 Leu163 and Val165 and phosphorylates CSN6 at Ser148.
COPS6 affects CDK9
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COPS6 activates CDK9.
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COPS6 activates CDK9. 3 / 3
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Next , western blot analysis demonstrated that CSN6 increased CDK9 expression and decreased UBR5 expression in a dose-dependent manner in 293FT cells ( Fig. 5B ) .

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We also found that CSN6 overexpression in melanoma cells could prolong the half-life of CDK9 and that the decrease in CDK9 protein expression in CSN6-knockdown cells could be obviously rescued in the presence of MG132, indicating that CSN6 regulates CDK9 stability by reducing CDK9 ubiquitination.

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Furthermore, in CSN6-knockdown melanoma cells, UBR5 knockdown abrogated the effects caused by CSN6 silencing, suggesting that CSN6 activates the UBR5 and CDK9 pathway to promote melanoma cell proliferation and metastasis.
COPS6 increases the amount of CDK9.
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COPS6 increases the amount of CDK9. 2 / 2
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Our study revealed that CSN6 positively regulated the CDK9 protein level, while the CDK9 mRNA level remained unchanged, indicating that CSN6 may regulate CDK9 expression through posttranscriptional regulation.

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Next, western blot analysis demonstrated that CSN6 increased CDK9 expression and decreased UBR5 expression in a dose dependent manner in 293FT cells.
COPS6 inhibits CDK9.
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COPS6 inhibits CDK9. 1 / 1
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Then, we explored how CSN6 affects the stability of CDK9 and found that overexpression of CSN6 decreased the turnover rate of CDK9 in melanoma cells by using the de novo protein synthesis inhibitor cycloheximide (CHX, Sigma, USA).
COPS6 decreases the amount of CDK9.
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COPS6 decreases the amount of CDK9. 1 / 1
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In addition, to investigate whether CSN6 controls the ubiquitination and degradation of the E3 ligase UBR5 to stabilize CDK9, in vivo ubiquitination assays were performed and found that CSN6 increased UBR5 ubiquitination levels and decreased CDK9 ubiquitination levels in melanoma cells and 293FT cells.
MAPK1 affects COPS6
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MAPK1 activates COPS6.
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MAPK1 activates COPS6. 3 / 4
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Taken together, our study 's findings indicate that the deregulation of beta-catenin by ERK2 activated CSN6 is important for CRC development.

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Fang et al. reported that ERK2-activated CSN6 regulates β-Trcp and stabilized β-catenin expression by blocking the ubiquitin-proteasome pathway, thereby promoting CRC development xref .

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Taken together, our study’s findings indicate that the deregulation of β-catenin by ERK2-activated CSN6 is important for CRC development.
MAPK1 decreases the amount of COPS6.
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MAPK1 decreases the amount of COPS6. 2 / 2
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Furthermore, we found that EGF treatment or ERK2 activation decreases the ubiquitination level of CSN6.

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Furthermore, we found that EGF treatment or ERK2 activation decreases the ubiquitination level of CSN6 (XREF_FIG).

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CSN6 induces EMT and enhances metastasis of breast cancer cells by reducing Snail1 ubiquitination .

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Additionally, CSN6 was found to promote EMT by inhibiting E-cadherin, which were significantly mitigated via upregulation of Snail as a result of MEK and ERK pathway activation.

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Together, the results suggest that CSN6 may positively regulate beta-catenin transcription, thereby mediating the EMT.

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CSN6 promotes PTC progression by inducing the EMT.
COPS6 increases the amount of epithelial to mesenchymal transition.
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CSN6 positively regulated beta-catenin expression in a beta-Trcp-dependent manner and triggered expression of several EMT related genes regulated by beta-catenin.

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CSN6 positively regulates beta-catenin expression in a beta-Trcp-dependent manner and triggers the expression of several EMT related genes regulated by beta-catenin.
COPS6 affects TRIM21
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COPS6 decreases the amount of TRIM21.
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COPS6 decreases the amount of TRIM21. 4 / 4
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In addition, knockdown of CSN6 increased TRIM21 protein levels.

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In HCT116 cells, CSN6 reduced the steady-state level of TRIM21, and MLN4924 treatment reversed this effect.

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45 Interestingly, CSN6 is able to decrease the steady-state expression of TRIM21 by enhancing TRIM21 ubiquitination, thereby promoting cancer stemness.

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We first identified that overexpression of CSN6 reduced the steady-state expression of TRIM21 in a dose dependent manner in the DLD-1 cell line.
COPS6 inhibits TRIM21.
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COPS6 inhibits TRIM21. 1 / 1
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Together, these results indicate that CSN6 promoted TRIM21 degradation is dependent on TRIM21 self ubiquitination via K48 ubiquitin linkage.
COPS6 increases the amount of TRIM21.
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COPS6 increases the amount of TRIM21. 1 / 1
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To further examine the role of CSN6 in regulating TRIM21 ubiquitination, we showed that overexpression of CSN6 increases the ubiquitination level of TRIM21.
COPS6 affects CDKN1B
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COPS6 inhibits CDKN1B.
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COPS6 inhibits CDKN1B. 3 / 3
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CSN6 mediated p27 degradation depends on the nuclear export of p27, which is regulated through COP1 's nuclear exporting signal.

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CSN6 mediated p27 degradation depends on the nuclear export of p27 (Kip1), which is regulated through COP1 nuclear exporting signal.

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Ectopic expression of CSN6 can decrease the expression of p27 (Kip1), while CSN6 knockdown leads to p27 (Kip1) stabilization.
COPS6 decreases the amount of CDKN1B.
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Modified COPS6 decreases the amount of CDKN1B. 2 / 2
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Ectopic expression of CSN6 decreases the expression of p27 while CSN6 knockdown leads to p27 stabilization.

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Ectopic expression of CSN6 can decrease the expression of p27 (Kip1), while CSN6 knockdown leads to p27 (Kip1) stabilization.
COPS6 activates CDKN1B.
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COPS6 activates CDKN1B. 1 / 1
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It is reported that CSN6 could stabilize the E3 ubiquitin ligase COP1 in human colorectal cancer cell line HCT116 and human embryonic kidney cell line HEK-293T, thereby accelerating the cyclin dependent protein kinase inhibitor p27 that involved in the G1 phase of cell cycle to regulate cell proliferation XREF_BIBR.
COPS6 affects CORO1A
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COPS6 activates CORO1A.
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COPS6 activates CORO1A. 2 / 2
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CSN6 associates with p57 (Kip2), and its overexpression can decrease the steady-state expression of p57 (Kip2); accordingly, CSN6 deficiency leads to p57 (Kip2) stabilization.

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CDK inhibitor p57 (Kip2) is negatively regulated by COP9 signalosome subunit 6.
COPS6 decreases the amount of CORO1A.
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Modified COPS6 decreases the amount of CORO1A. 1 / 1
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These data suggest that CSN6 is an important negative regulator of p57 (Kip2), and that overexpression of CSN6 in many types of cancer could lead to decreased expression of p57 (Kip2) and result in promoted cancer cell growth.
COPS6 decreases the amount of CORO1A. 1 / 1
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CSN6 associates with p57 (Kip2), and its overexpression can decrease the steady-state expression of p57 (Kip2); accordingly, CSN6 deficiency leads to p57 (Kip2) stabilization.
COPS6 inhibits CORO1A.
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COPS6 inhibits CORO1A. 1 / 1
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Loss of Skp2 compromised CSN6 mediated p57 (Kip2) destabilization, suggesting collaboration between Skp2 and CSN6 in degradation of p57 (Kip2).
COPS6 increases the amount of CORO1A.
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COPS6 increases the amount of CORO1A. 1 / 1
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found that CSN6 was involved in p57 downregulation and increased the ubiquitination level of p57 in a dose dependent manner.
COPS6 affects ptc
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COPS6 activates ptc. 5 / 5
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In vitro and in vivo data showed that loss of CSN6 attenuated cell proliferation, migration, and invasion of PTC cells, confirming the vital function of CSN6 in PTC.

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CSN6 promotes PTC progression by inducing the EMT.

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Second, functional assays showed that CSN6 inhibition significantly reduced both the motility and the proliferation of PTC cells.

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Thus, loss of CSN6 expression inhibits PTC proliferation and migration.

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These results suggest that CSN6 robustly modulates PTC migration and invasiveness.
COPS6 affects SIRT2
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COPS6 inhibits SIRT2.
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COPS6 inhibits SIRT2. 3 / 3
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Further investigation discovered that CSN6 suppressed the expression of SIRT2 via up-regulating Nkx2.2 , a transcription suppressor of SIRT2 .

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CSN6 inhibited the expression of SIRT2 , and re-expression of SIRT2 attenuated the myocardial hypertrophy caused by CSN6 overexpression .

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Finally, our data showed that CSN6 was partially dependent on the stabilization of Nkx2.2 protein to inhibit SIRT2 and promote myocardial hypertrophy.
COPS6 decreases the amount of SIRT2.
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COPS6 decreases the amount of SIRT2. 2 / 2
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CSN6 inhibited the expression of SIRT2, and re-expression of SIRT2 attenuated the myocardial hypertrophy caused by CSN6 overexpression.

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Further investigation discovered that CSN6 suppressed the expression of SIRT2 via up-regulating Nkx2.2, a transcription suppressor of SIRT2.
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Pirinixic acid increases the amount of COPS6. 4 / 4
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COPS6 affects cell growth
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MTT and BrdU assays revealed that recovery of CSN6 expression rescued cell growth and proliferation.

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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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Also, CSN6 overexpression leads to increased cell growth, transformation and promotes tumorigenicity.
COPS6 affects FBXW7
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COPS6 decreases the amount of FBXW7.
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COPS6 decreases the amount of FBXW7. 2 / 2
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Compared with wt CSN6, which clearly decreased Fbxw7 expression and increased Myc expression in U2OS cells, the MPN-KQV CSN6 mutant lost these functions (XREF_SUPPLEMENTARY).

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It is important to point out that CSN6 interacted with all the three isoforms of Fbxw7 XREF_BIBR, XREF_BIBR and reduced the steady-state expression of Fbxw7 in a dose dependent manner (XREF_SUPPLEMENTARY).
COPS6 activates FBXW7.
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COPS6 activates FBXW7. 2 / 2
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Consistently, CSN6 knockdown decreased turnover rate of Fbxw7 (XREF_FIG and XREF_SUPPLEMENTARY).

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We next addressed whether Cullin-1 is involved in CSN6 mediated Fbxw7 downregulation.
COPS6 affects EGFR
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COPS6 increases the amount of EGFR.
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COPS6 increases the amount of EGFR. 1 / 3
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Moreover, CSN6 decreased CHIP expression and increased EGFR expression in the tumor samples.
COPS6 decreases the amount of EGFR.
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COPS6 decreases the amount of EGFR. 1 / 1
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Moreover, CSN6 decreased CHIP expression and increased EGFR expression in the tumor samples.
COPS6 affects ALDH1A1
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COPS6 increases the amount of ALDH1A1.
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COPS6 increases the amount of ALDH1A1. 3 / 3
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Importantly, CSN6 caused an increase in the Aldh1a1 mRNA level and that overexpression of TRIM21 led to a decrease in the Aldh1a1 mRNA level, even in the presence of CSN6.

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40 Interestingly, CSN6 is able to promote the expression of ALDH1A1, a known CSC marker upregulated in cancer spheroids.

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We found that the expression of CSN6 increased the steady-state protein expression levels of OCT1 and ALDH1A1, with a concurrent reduction in TRIM21 expression in a dose dependent manner.
COPS6 activates ALDH1A1.
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COPS6 activates ALDH1A1. 1 / 1
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Cells with high ALDH1A1 levels have increased expression levels of vimentin , matrix metalloproteinase-2 ( MMP2 ) , MMP7 and MMP9 , which are implicated in epithelial-mesenchymal transition and metastatic capabilities.40 Interestingly , CSN6 is able to promote the expression of ALDH1A1 , a known CSC marker upregulated in cancer spheroids.41 Chromatin immunoprecipitation assays have characterised ALDH1A1 as a direct target of beta-catenin activation .
COPS6 affects POU2F1
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COPS6 decreases the amount of POU2F1.
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COPS6 decreases the amount of POU2F1. 2 / 2
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We found that overexpression of CSN6 reduced the ubiquitination level of OCT1.

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Consistent with this finding, we found that knockdown of CSN6 increased the ubiquitination level of OCT1.
COPS6 inhibits POU2F1.
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COPS6 inhibits POU2F1. 1 / 1
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Indeed, CSN6 knockdown led to decelerated turnover of TRIM21 but accelerated turnover of OCT1.
COPS6 increases the amount of POU2F1.
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COPS6 increases the amount of POU2F1. 1 / 1
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We found that the expression of CSN6 increased the steady-state protein expression levels of OCT1 and ALDH1A1, with a concurrent reduction in TRIM21 expression in a dose dependent manner.
COPS6 affects CUL
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COPS6 activates CUL.
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COPS6 activates CUL. 2 / 2
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We find that CSN6 enhanced Cullin neddylation facilitates auto-ubiquitination and degradation of Myc E3 ligase Fbxw7, thereby stabilizing Myc, indicates that CSN6 is a positive upstream regulator of Myc.

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CSN6 competes with CSN5 to increase Cullin neddylation.
COPS6 inhibits CUL.
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COPS6 bound to CUL inhibits CUL. 1 / 1
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On the other hand, it is conceivable that in CSN6 overexpressing cancers abundant CSN6 binds more amounts of Cullin and thus reduces the accessibility of Cullin to CSN5 for deneddylation, thereby preserving Cullin neddylation.
COPS6 increases the amount of CUL.
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COPS6 increases the amount of CUL. 1 / 1
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In a side-by-side comparison of fractions of Csn6 +/- and Csn6 +/+ mouse spleen cell extracts, we observed high CSN5 and CSN6 ratios in fractions of Csn6 +/- cell extracts, which in turn led to increased amounts of non neddylated Cullin.
MYC affects COPS6
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MYC activates COPS6. 3 / 3
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CSN6 increase Myc stability by reducing Myc ubiquitination.

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A recent study also demonstrated that CSN6 contributed to carcinogenesis by positive regulation of Myc stability.

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As expected, Myc mediated transcriptional activation target CDK4 and Myc mediated transcriptional repression targets p27Kip1 and p21Cip1 were deregulated in Emicro-Myc and Csn6 +/- lymphomas compared to Emicro-Myc and Csn6 +/+ lymphomas (XREF_FIG).
COPS6 affects quercetin
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The overexpression of CSN6 reduced the effect of quercetin treatment on HT-29 cells, suggesting that quercetin induced apoptosis may involve the Akt-CSN6-Myc signaling axis in HT-29 cells.

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The MTT assay revealed that the overexpression of CSN6 reduced the effect of quercetin on cell viability compared with the empty plasmid MIGR1 (XREF_FIG).

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The MTT assay revealed that the overexpression of CSN6 reduced the effect of quercetin on cell viability compared with the empty MIGR1 plasmid (XREF_FIG).
| 3

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CSN6 knockdown also accelerated apoptosis as evident in increased sub-G1 population after propidium iodide staining followed by flow cytometry.

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Through combinatorial effects on the MDM2-p53 signaling axis and now SKP2 mediated p57 Kip2 degradation, it is hypothesized that CSN6 overexpression can effectively promote cell proliferation by simultaneously relieving cell cycle restraints, apoptosis, senescence, and presumably p53 functions in DNA damage repair and cell metabolism, among other important tumor suppressive mechanisms.

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CSN6 knockdown increased apoptosis as evident in increased Annexin V staining when compared with vector control.
COPS6 affects ERVK-10
| 2 1
| 2 1

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We further demonstrated CSN6 inhibited integrase activity in vitro; knockdown of CSN6 in DF-1 promoted ALV production.

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COP9 signalosome subunit 6 binds and inhibits avian leukosis virus integrase.

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We further demonstrated CSN6 inhibited integrase activity in vitro; knockdown of CSN6 in DF-1 promoted ALV production.
Quercetin affects COPS6
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Quercetin inhibits COPS6.
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Western blot analysis revealed that quercetin reduced the protein expression levels of phosphorylated-Akt and increased CSN6 protein degradation; therefore, affecting the expression levels of Myc, p53, B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein.
Quercetin decreases the amount of COPS6.
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Quercetin decreases the amount of COPS6. 1 / 1
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The present study determined that quercetin may reduce the protein expression levels of CSN6 in HT-29 colon cancer cells and that it may be one of the important targets for quercetin induced apoptosis in HT-29 cells.
COPS6 affects cell cycle
| 3
COPS6 inhibits cell cycle.
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Through combinatorial effects on the MDM2-p53 signaling axis and now SKP2 mediated p57 Kip2 degradation, it is hypothesized that CSN6 overexpression can effectively promote cell proliferation by simultaneously relieving cell cycle restraints, apoptosis, senescence, and presumably p53 functions in DNA damage repair and cell metabolism, among other important tumor suppressive mechanisms.

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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.
COPS6 activates cell cycle.
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| 1

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This study revealed that CSN6 knockdown in melanoma cells inhibited cell proliferation in vitro and tumorigenicity in mice by inducing cell cycle arrest and that the anti-proliferative effect could be rescued by overexpressing CSN6 in CSN6-knockdown melanoma cells, suggesting that CSN6 has critical roles in triggering melanoma initiation and progression.
COPS6 affects STUB1
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COPS6 decreases the amount of STUB1.
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COPS6 decreases the amount of STUB1. 2 / 2
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Moreover, CSN6 decreased CHIP expression and increased EGFR expression in the tumor samples.

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Inhibition of CSN6 by small interfering RNA decreased PD-L1 expression but also increased CHIP expression in GBM cells.
COPS6 increases the amount of STUB1.
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COPS6 increases the amount of STUB1. 1 / 1
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Inhibition of CSN6 by small interfering RNA decreased PD-L1 expression but also increased CHIP expression in GBM cells.
COPS6 affects SNAI1
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COPS6 activates SNAI1.
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COPS6 activates SNAI1. 2 / 2
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Ubiquitination assay was performed to validate whether ubiquitination is involved in the upregulation of Snail1 by CSN6 .

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Thus , we speculated that CSN6 induced up-regulation of Snail may be regulated at the post-transcriptional level .
COPS6 inhibits SNAI1.
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COPS6 inhibits SNAI1. 1 / 1
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Our study showed that CSN6 prevented Snail1 degradation via proteasomal degradation .
COPS6 affects COPS5
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COPS6 activates COPS5.
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COPS6 activates COPS5. 1 / 2
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To gain additional insights into the molecular mechanism of CSN5 activation by CSN6, the crystal structure of the MPN − core fragment was determined by molecular replacement at 1.76 Å resolution, using the human Rpn8 ΔC orthologue as the search model (PDB code 2O95; xref ).
COPS6 inhibits COPS5.
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COPS6 inhibits COPS5. 1 / 1
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Notably, the MPN domain of CSN6 inhibited the association of CSN5 with Cullin-1, while the C-terminal domain had less impact (XREF_FIG).
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Cobalt dichloride decreases the amount of COPS6. 2 / 2
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MAP2K1 affects COPS6
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Modified MAP2K1 increases the amount of COPS6. 2 / 2
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In addition, the expression of a constitutively active MEK1 (MEK1 CA) increased CSN6 expression in DLD-1 cells.

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In addition, the expression of a constitutively active MEK1 (MEK1 CA) increased CSN6 expression in DLD-1 cells (XREF_SUPPLEMENTARY).
COPS6 affects TIMP2
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COPS6 activates TIMP2. 2 / 2
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Bioinformatics and Luciferase reporter genes demonstrated that CSN6 can target the corresponding sites of TIMP-2 promoter.

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Additionally, we verified that CSN6 may promote OSCC malignant progression by regulating TIMP-2.
COPS6 affects Neoplasms
| 1
| 1

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It has been reported that CSN6 can promote some degree of tumor progression by regulating the stability of several E3 ligases6-8 ,21 .
COPS6 affects Melanoma
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| 2

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CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9 As a critical subunit of the constitutive photomorphogenesis 9 ( COP9 ) signalosome ( CSN ) , CSN6 is upregulated in some human cancers and plays critical roles in tumorigenesis and progression , but its biological functions and molecular mechanisms in melanoma remain unknown .

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CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9 .
COPS6 affects MDM2
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COPS6 activates MDM2. 2 / 2
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CSN6 may promote carcinogenesis by positively regulating v-myc avian myelocytomatosis viral oncogene homolog (Myc) and MDM2 proto-oncogene stability, and is regarded as a potential target for cancer therapy.

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Previously, Lee 's laboratory demonstrated that CSN6, a subunit of the COP9 signalosome, interacts with and inhibits the degradation of an oncogene MDM2, leading to its stabilization (XREF_FIG).
COPS6 affects MAP3K1
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COPS6 decreases the amount of MAP3K1. 1 / 2
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Here, we show that CSN6 associates with MEKK1 and reduces MEKK1 expression level by facilitating the ubiquitin mediated degradation of MEKK1.
COPS6 affects EGF
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COPS6 activates EGF. 2 / 2
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CSN6 mRNA levels did not increase significantly in response to EGF (XREF_SUPPLEMENTARY), suggesting that EGF regulates CSN6 posttranslationally.

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CSN6 mRNA levels did not increase significantly in response to EGF, suggesting that EGF regulates CSN6 posttranslationally.
| 2
| 2

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For example, CSN6, a component of the COP9 signalosome, positively regulate E3 ubiquitin ligases.

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It has been reported that CSN6 can promote some degree of tumor progression by regulating the stability of several E3 ligases XREF_BIBR - XREF_BIBR, XREF_BIBR.
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(D-Phe2) VIP, VIP [10-28], VIP [16-28], and (p-Cl-D-Phe6, Leu17) VIP, a putative VIP receptor antagonist, affected neither basal cAMP levels nor hVIP induced cAMP accumulation.

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The ability of hVIP and analogues to stimulate cAMP generation paralleled their potencies in displacing 125I-VIP binding.
17alpha-ethynylestradiol increases the amount of COPS6. 2 / 2
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ctd
No evidence text available

ctd
No evidence text available
Bisphenol A affects COPS6
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Bisphenol A increases the amount of COPS6.
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Bisphenol A increases the amount of COPS6. 1 / 1