https://scholars.lib.ntu.edu.tw/handle/123456789/361382
標題: | Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers. | 作者: | You-Tzung Chen Yeung S.-C.J. Chen J. Iwakuma T. Su C.-H. Chen B. Qu C. Zhang F. YOU-TZUNG CHEN Lin Y.-L. Lee D.-F. Jin F. Zhu R. Shaikenov T. Sarbassov D. Sahin A. Wang H. Wang H. Lai C.-C. Tsai F.-J. Lozano G. Lee M.-H. |
公開日期: | 三月-2011 | 摘要: | 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. |
URI: | http://europepmc.org/abstract/med/21317535 http://scholars.lib.ntu.edu.tw/handle/123456789/361382 |
DOI: | 10.1172/JCI44111 | SDG/關鍵字: | COP9 signalosome; protein MDM2; protein p53; protein subunit; animal cell; apoptosis; article; breast cancer; carcinogenesis; cell cycle regulation; controlled study; DNA damage; embryo development; gamma irradiation; gene amplification; gene locus; human; human tissue; mouse; nonhuman; priority journal; protein expression; signal transduction; thyroid carcinoma; thyroid tumor; upregulation; Animals; Breast Neoplasms; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Transgenic; Multiprotein Complexes; Peptide Hydrolases; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Thyroid Gland; Tumor Suppressor Protein p53; Up-Regulation |
顯示於: | 基因體暨蛋白體醫學研究所 |
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