Gene Summary

Gene:COPS6; COP9 signalosome subunit 6
Aliases: CSN6, MOV34-34KD
Summary:The protein encoded by this gene is one of the eight subunits of COP9 signalosome, a highly conserved protein complex that functions as an important regulator in multiple signaling pathways. The structure and function of COP9 signalosome is similar to that of the 19S regulatory particle of 26S proteasome. COP9 signalosome has been shown to interact with SCF-type E3 ubiquitin ligases and act as a positive regulator of E3 ubiquitin ligases. This protein belongs to translation initiation factor 3 (eIF3) superfamily. It is involved in the regulation of cell cycle and likely to be a cellular cofactor for HIV-1 accessory gene product Vpr. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:COP9 signalosome complex subunit 6
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: COPS6 (cancer-related)

Wang W, Tang M, Zhang L, et al.
Clinical implications of CSN6 protein expression and correlation with mutant-type P53 protein in breast cancer.
Jpn J Clin Oncol. 2013; 43(12):1170-6 [PubMed] Related Publications
OBJECTIVE: Constitutive photomorphogenesis 9 subunit 6, as one subunit of the constitutive photomorphogenesis 9, plays an important role in tumor development. The aim of the study was to investigate the clinical and prognostic implications of constitutive photomorphogenesis 9 subunit 6 protein in breast cancer.
METHODS: We examined mastectomy specimens from 92 invasive breast cancers and matched with 20 adjacent non-cancerous tissues using immunohistochemistry.
RESULTS: The positive expressions of constitutive photomorphogenesis 9 subunit 6 protein in invasive breast cancer and adjacent non-cancerous tissue were 32.61% (30 of 92) and 10% (2 of 20), respectively. The positive expression of constitutive photomorphogenesis 9 subunit 6 protein was related to tumor size, histological type and lymph node metastasis (P = 0.015, 0.009 and 0.009, respectively). After univariate analysis, constitutive photomorphogenesis 9 subunit 6-positive expression was only found to be significantly related to mutant-type P53 expression (P < 0.001). Spearman's correlation analysis was used to demonstrate negative correlations between constitutive photomorphogenesis 9 subunit 6 and mutant-type P53 (r = -0.417). Constitutive photomorphogenesis 9 subunit 6 positive was associated with both poorer breast cancer-specific survival in 92 cases and in the lymph node-positive group (P = 0.007 and 0.024, respectively). In the Cox regression test, constitutive photomorphogenesis 9 subunit 6 protein was not shown to be an independent prognostic factor for breast cancer.
CONCLUSION: Constitutive photomorphogenesis 9 subunit 6 might be a new potential biomarker for breast cancer. However, the underlying mechanisms of constitutive photomorphogenesis 9 subunit 6's involvement are still unclear.

Lee MH, Zhao R, Phan L, Yeung SC
Roles of COP9 signalosome in cancer.
Cell Cycle. 2011; 10(18):3057-66 [PubMed] Free Access to Full Article Related Publications
The constitutive photomorphogenesis 9 signalosome (COP9 or CSN) is an evolutionarily conserved multiprotein complex found in plants and animals. Because of the homology between the COP9 signalosome and the 19S lid complex of the proteosome, COP9 has been postulated to play a role in regulating the degradation of polyubiquitinated proteins. Many tumor suppressor and oncogene products are regulated by ubiquitination- and proteosome-mediated protein degradation. Therefore, it is conceivable that COP9 plays a significant role in cancer, regulating processes relevant to carcinogenesis and cancer progression (e.g., cell cycle control, signal transduction and apoptosis). In mammalian cells, it consists of eight subunits (CSN1 to CSN8). The relevance and importance of some subunits of COP9 to cancer are emerging. However, the mechanistic regulation of each subunit in cancer remains unclear. Among the CSN subunits, CSN5 and CSN6 are the only two that each contain an MPN (Mpr1p and Pad1p N-terminal) domain. The deneddylation activity of an MPN domain toward cullin-RING ubiquitin ligases (CRL) may coordinate CRL-mediated ubiquitination activity. More recent evidence shows that CSN5 and CSN6 are implicated in ubiquitin-mediated proteolysis of important mediators in carcinogenesis and cancer progression. Here, we discuss the mechanisms by which some CSN subunits are involved in cancer to provide a much needed perspective regarding COP9 in cancer research, hoping that these insights will lay the groundwork for cancer intervention.

Zhao R, Yeung SC, Chen J, et al.
Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers.
J Clin Invest. 2011; 121(3):851-65 [PubMed] Free Access to Full Article Related Publications
The mammalian constitutive photomorphogenesis 9 (COP9) signalosome (CSN), a protein complex involved in embryonic development, is implicated in cell cycle regulation and the DNA damage response. Its role in tumor development, however, remains unclear. Here, we have shown that the COP9 subunit 6 (CSN6) gene is amplified in human breast cancer specimens, and the CSN6 protein is upregulated in human breast and thyroid tumors. CSN6 expression positively correlated with expression of murine double minute 2 (MDM2), a potent negative regulator of the p53 tumor suppressor. Expression of CSN6 appeared to prevent MDM2 autoubiquitination at lysine 364, resulting in stabilization of MDM2 and degradation of p53. Mice in which Csn6 was deleted died early in embryogenesis (E7.5). Embryos lacking both Csn6 and p53 survived to later in embryonic development (E10.5), which suggests that loss of p53 could partially rescue the effect of loss of Csn6. Mice heterozygous for Csn6 were sensitized to γ-irradiation-induced, p53-dependent apoptosis in both the thymus and the developing CNS. These mice were also less susceptible than wild-type mice to γ-irradiation-induced tumorigenesis. 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.

van Dekken H, Tilanus HW, Hop WC, et al.
Array comparative genomic hybridization, expression array, and protein analysis of critical regions on chromosome arms 1q, 7q, and 8p in adenocarcinomas of the gastroesophageal junction.
Cancer Genet Cytogenet. 2009; 189(1):37-42 [PubMed] Related Publications
Survival rates of adenocarcinomas of the gastroesophageal junction (GEJ) are low, because these tumors are generally in an advanced stage by the time they are detected. Chromosomal regions 1q32, 7q21, and 8p22 display critical alterations in GEJ cancers; however, the genes underlying alterations in these genomic areas are largely unknown. To delineate overexpressed genes, we performed array comparative genomic hybridization (aCGH) and mRNA expression analysis of 15 GEJ adenocarcinoma samples using a fine-tiling cDNA array covering chromosome segments 1q31.3~q41 (193.9-215.8 Mb: 21.9 Mb), 7q11.23~q22.1 (72.3-103.0 Mb: 30.7 Mb), and 8p23.1~p21.3 (11.1-20.7 Mb: 9.6 Mb). Based on a mRNA overexpression criterion, 11 genes were selected: ELF3 and SLC45A3 on 1q; CLDN12, CDK6, SMURF1, ARPC1B, ZKSCAN1, MCM7, and COPS6 on 7q; and FDFT1 and CTSB on 8p. The protein expression levels were subsequently determined by immunohistochemical analysis of the cancer samples. There was a significant correlation between genomic amplification, mRNA, and protein expression or overexpression for CDK6, a cell cycle regulator on 7q21.2 (92.1 Mb; P<0.01); other genes showed less stringent associations. In conclusion, using a straightforward approach we constructed a targeted gene profile for GEJ adenocarcinomas.

Gemmill RM, Lee JP, Chamovitz DA, et al.
Growth suppression induced by the TRC8 hereditary kidney cancer gene is dependent upon JAB1/CSN5.
Oncogene. 2005; 24(21):3503-11 [PubMed] Related Publications
TRC8 encodes an E3-ubiquitin ligase disrupted in a family with hereditary renal cell carcinoma (RCC). We previously reported that Drosophila Trc8 (DTrc8) overexpression inhibits growth and that human and fly proteins interact with with the COP9 signalosome (CSN) subunit JAB1/CSN5. However, further mechanistic evidence linking DTrc8 growth suppression to CSN5 was lacking. Here, we show that haploinsufficiency of CSN5, or a T100I point mutation (CSN5(3)), relieved growth suppression by DTrc8, whereas CSN5(1) (E160V) and CSN5(2) (G147D) mutations had no effect. The strength of yeast two-hybrid interactions between DTrc8 and CSN5 were in complete agreement with the observed phenotypes. DTrc8 overexpression resulted in elevated levels of CSN5 and CSN7, but had no effect on NEDD8-modified Cul-1. In contrast to CSN5, heterozygosity for CSN4null had no effect on the DTrc8 phenotype. We also looked for genetic interactions between DTrc8 and other MPN domain proteins in the CSN and 26S proteasome lid. CSN6 haploinsufficiency restored growth, whereas reduction of proteasome subunits RPN8 or RPN11 had no effect. DTrc8 expression increased the level of digitonin-extractable CSN complex, consistent with elevated levels of CSN5 and 7. Our genetic results confirm that DTrc8-induced growth suppression is CSN5 (and CSN6) dependent. While there was no obvious influence on CSN deneddylation activity, the increase in CSN subunits and holocomplex suggests that TRC8 modulates signalosome levels or compartmentalization.

Chen J, Shin JH, Zhao R, et al.
CSN6 drives carcinogenesis by positively regulating Myc stability.
Nat Commun. 2014; 5:5384 [PubMed] Article available free on PMC after 14/05/2015 Related Publications
Cullin-RING ubiquitin ligases (CRLs) are critical in ubiquitinating Myc, while COP9 signalosome (CSN) controls neddylation of Cullin in CRL. The mechanistic link between Cullin neddylation and Myc ubiquitination/degradation is unclear. Here we show that Myc is a target of the CSN subunit 6 (CSN6)-Cullin signalling axis and that CSN6 is a positive regulator of Myc. CSN6 enhanced neddylation of Cullin-1 and facilitated autoubiquitination/degradation of Fbxw7, a component of CRL involved in Myc ubiquitination, thereby stabilizing Myc. Csn6 haplo-insufficiency decreased Cullin-1 neddylation but increased Fbxw7 stability to compromise Myc stability and activity in an Eμ-Myc mouse model, resulting in decelerated lymphomagenesis. We found that CSN6 overexpression, which leads to aberrant expression of Myc target genes, is frequent in human cancers. Together, these results define a mechanism for the regulation of Myc stability through the CSN-Cullin-Fbxw7 axis and provide insights into the correlation of CSN6 overexpression with Myc stabilization/activation during tumorigenesis.

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Cite this page: Cotterill SJ. CSN6 (COPS6), Cancer Genetics Web: Accessed:

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