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Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers.

ABSTRACT: 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 ?-irradiation-induced, p53-dependent apoptosis in both the thymus and the developing CNS. These mice were also less susceptible than wild-type mice to ?-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.

SUBMITTER: Zhao R

PROVIDER: S-EPMC3049400 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers.

Zhao Ruiying R Yeung Sai-Ching J SC Chen Jian J Iwakuma Tomoo T Su Chun-Hui CH Chen Bo B Qu Changju C Zhang Fanmao F Chen You-Tzung YT Lin Yu-Li YL Lee Dung-Fang DF Jin Feng F Zhu Rui R Shaikenov Tattym T Sarbassov Dos D Sahin Aysegul A Wang Huamin H Wang Hua H Lai Chien-Chen CC Tsai Fuu-Jen FJ Lozano Guillermina G Lee Mong-Hong MH

The Journal of clinical investigation 20110207 3

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 mi ...[more]

PMID: 21317535

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Project description:ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) play a vital role in promoting cholesterol efflux. Although, the dysregulation of these transporters was attributed as one of the mechanisms of atherogenesis, what renders their dysfunction is not well explored. Previously, we have reported that thrombin without having any effect on ABCG1 levels depletes ABCA1 levels affecting cholesterol efflux. In this study, we explored the mechanisms underlying thrombin-induced depletion of ABCA1 levels both in macrophages and smooth muscle cells. Under normal physiological conditions, COP9 signalosome subunit 3 (CSN3) was found to exist in complex with ABCA1 and in the presence of proatherogenic stimulants such as thrombin, ABCA1 was phosphorylated and dissociated from CSN3, leading to its degradation. Forced expression of CSN3 inhibited thrombin-induced ABCA1 ubiquitination and degradation, restored cholesterol efflux and suppressed foam cell formation. In Western diet (WD)-fed ApoE-/- mice, CSN3 was also disassociated from ABCA1 otherwise remained as a complex in Chow diet (CD)-fed ApoE-/- mice. Interestingly, depletion of CSN3 levels in WD-fed ApoE-/- mice significantly lowered ABCA1 levels, inhibited cholesterol efflux and intensified foam cell formation exacerbating the lipid laden atherosclerotic plaque formation. Mechanistic studies have revealed the involvement of Par1-Gα12-Pyk2-Gab1-PKCθ signaling in triggering phosphorylation of ABCA1 and its disassociation from CSN3 curtailing cholesterol efflux and amplifying foam cell formation. In addition, although both CSN3 and ABCA1 were found to be colocalized in human non-lesion coronary arteries, their levels were decreased as well as dissociated from each other in advanced atherosclerotic lesions. Together, these observations reveal for the first time an anti-atherogenic role of CSN3 and hence, designing therapeutic drugs protecting its interactions with ABCA1 could be beneficial against atherosclerosis.

Project description:Background: The COP9 signalosome (CSN) consisting of 8 protein subunits (CSN1 through CSN8) is a deneddylase for Cullin-RING ligases (CRLs), essential to the functioning of the ubiquitin-proteasome system. CSN8 is encoded by the Cops8 gene. We have shown that CSN8 plays a key role in the regulation of cardiac protein quality control (PQC), and cardiomyocyte-restricted Cops8 knockout (CSN8-CKO) in perinatal and adult mice causes massive cardiomyocyte necrosis and acute heart failure in mice. Objective: To identify the underlying mechanisms at the transcriptional level, we examined the impact of perinatal CSN8-CKO on myocardial gene expression. Design: Whole mouse genome DNA microarrays (CodeLink) were used to assess myocardial gene expression profiles in Control (CTL), heterozygous (Het-CKO), and homozygous (Hom-CKO) cardiac Cops8 knockout littermate mice at 2- and 3-weeks-of-age. GeneSpring GS software (v.12.5) was used to analyze differentially expressed genes (DEGs). DEGs were analyzed using the GeneGo MetaCore Analytical Suite (http://genego.com; GeneGo, St. Joseph, MI) to identify significantly enriched pathways. Network analysis was performed using R package WGCNA on the expression profiles of DEGs. IPA analysis was also performed. Results: The microarray data revealed 521 DEGs at 3-weeks-of-age with cut-off log2 |fold change|≧1. Among these genes, 271 genes were upregulated and 250 were downregulated. Similarly, at 2-weeks-of-age, out of 78 DEG, 35 genes were upregulated and 43 were downregulated. The transcript levels of many substrate receptors of CRLs (Fbxo14, Fbxo31, Klhdc1, Klhdc7a, Klh31, Klh41) were significantly down-regulated by CSN8-CKO. Consistent with cardiac pathology and prior RNA dot blot analysis results, the microarray analysis revealed significant upregulation of fetal genes (e.g., Nppa, Nppb, Acta1) and down-regulation of many postnatal genes (Actc1, Atp2a2, Pln, Tpm1). Our results suggest that CSN8-CKO-induced decrease in cardiac contractility could be due to decreased transcription of cacna1s, ptgfr and mylk2 genes. Pathways related to cellular stress particularly oxidative stress and vesicular trafficking were also observed to be enriched following CSN8 deficiency in cardiomyocytes. Enrichment of DEGs in chromatin remodeling pathway corroborates the involvement of CSN8 in gene expression regulation. Conclusions: Myocardial gene expression profiles are dynamically affected by CSN8-CKO in mice. Our data strongly suggest that CSN8 is involved in the regulation of myocardial gene expression programs that regulate ubiquitination, chromatin remodeling, and vesicle trafficking in cardiomyocytes.

Dataset Information

Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers.

Publications

Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers.

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