title: 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 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.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ruiying
authors.initials: R
authors.lastname: Zhao
authors.forename: Sai-Ching J
authors.initials: SC
authors.lastname: Yeung
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Su
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Changju
authors.initials: C
authors.lastname: Qu
authors.forename: Fanmao
authors.initials: F
authors.lastname: Zhang
authors.forename: You-Tzung
authors.initials: YT
authors.lastname: Chen
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Lin
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Tattym
authors.initials: T
authors.lastname: Shaikenov
authors.forename: Dos
authors.initials: D
authors.lastname: Sarbassov
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.forename: Mong-Hong
authors.initials: MH
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000603300:Cops6 protein, mouse; D046912:Multiprotein Complexes; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex