Roles of COP9 signalosome in cancer

Figures & data

Figure 1 Transcriptomic analyses of CSN5 and CSN6 overexpression in human cancer patients. Human cancer patient data sets were obtained from Oncomine and Gene Expression Omnibus. Data were analyzed using Oncomine analysis tools and Nexus Expression 2.0. Only patients with more than 40% increase in CSN5 (A) or CSN6 (B) mRNA levels compared with normal tissues were scored as “CSN5 overexpression” or “CSN6 overexpression,” respectively. N represented the total number of patients analyzed in each type of cancer.

Figure 2 A model for the role of CSN6 in regulating MDM2-p53 axis. MDM2 is self-ubiquitinated at K346, which leads to fast turnover. CSN6 binds to MDM2 at a region 294–384 aa, potentially blocking MDM2-mediated self-ubiquitination at K346 site. Thus, MDM2 is more stable and can enhance p53 ubiquitination, which, in turn, will block p53-mediated biological functions.

Table 1 Targeted gene disruption studies of COP9 signalosome gene

Gene name	Phenotypes	Functional studies/references
CSN2	embryonic lethal; embryos die at E3.5; heterozygous mice survive well.	Abnormal elevation of cyclin E in csn2^−/− embryos; csn2^−/− embryos have elevated levels of p53 and p21.93
CSN3	embryonic lethal; embryos die at E8.5; heterozygous mice survive well.	csn3^−/− embryos have increased cell death but no cell proliferation.94
CSN5	embryonic lethal; embryos die at E8.5; heterozygous mice survive well; act as a regulator of p27, p53 and cyclin E.	csn5^+/− MEF demonstrated impaired cell growth; transgenic expression of csn5 rescues the csn5^−/− embryonic lethality; csn5 transgenic mice develop myeloproliferative disorders.74,91
CSN6	embryonic lethal; embryos die at E7.5; heterozygous mice survive well; act as a negative regulator of p53 and positive regulator of MDM2.	csn6-deficiency enhances p53-mediated apoptosis; loss of csn6 attenuates IR-induced tumorigenesis; embryonic lethality is partially rescued in p53 null background.6
CSN8	embryonic lethal; embryos die at E7.5; heterozygous mice survive well; E7.5 embryo demonstrated retarded growth and differentiation.	Loss of csn8 impairs peripheral T cell homeostasis; csn8-deficient T cells demonstrate compromised TCR-dependent response.95

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