Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers
Ruiying Zhao, Sai-Ching J. Yeung, Jian Chen, Tomoo Iwakuma, Chun-Hui Su, Bo Chen, Changju Qu, Fanmao Zhang, You-Tzung Chen, Yu-Li Lin, Dung-Fang Lee, Feng Jin, Rui Zhu, Tattym Shaikenov, Dos Sarbassov, Aysegul Sahin, Huamin Wang, Hua Wang, Chien-Chen Lai, Fuu-Jen Tsai, Guillermina Lozano, Mong-Hong Lee
Ruiying Zhao, Sai-Ching J. Yeung, Jian Chen, Tomoo Iwakuma, Chun-Hui Su, Bo Chen, Changju Qu, Fanmao Zhang, You-Tzung Chen, Yu-Li Lin, Dung-Fang Lee, Feng Jin, Rui Zhu, Tattym Shaikenov, Dos Sarbassov, Aysegul Sahin, Huamin Wang, Hua Wang, Chien-Chen Lai, Fuu-Jen Tsai, Guillermina Lozano, Mong-Hong Lee
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Research Article Oncology

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

Ruiying Zhao, Sai-Ching J. Yeung, Jian Chen, Tomoo Iwakuma, Chun-Hui Su, Bo Chen, Changju Qu, Fanmao Zhang, You-Tzung Chen, Yu-Li Lin, Dung-Fang Lee, Feng Jin, Rui Zhu, Tattym Shaikenov, Dos Sarbassov, Aysegul Sahin, Huamin Wang, Hua Wang, Chien-Chen Lai, Fuu-Jen Tsai, Guillermina Lozano, Mong-Hong Lee

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Figure 6

Csn6-deficient mice die in early embryogenesis.

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Csn6-deficient mice die in early embryogenesis. (A) Representative ...
(A) Representative phenotypes of Csn6–/– mouse embryos at different embryonic stages. Note that the Csn6–/– embryo had normal size and appearance on E7.5, but empty deciduae with little embryonic tissue were found on E8.5. Representative PCR genotyping results of these embryos are shown. (B) Csn6 protein expression in representative tissues of Csn6+/– and Csn6+/+ mice. (C) Ubiquitination status of p53 and Mdm2 in primary Csn6+/– and Csn6+/+ MEFs. Polyubiquitinated p53 or polyubiquitinated Mdm2 was immunoprecipitated with anti-p53 or anti-Mdm2, then probed with anti-ubiquitin. Equal amounts of TCE were immunoblotted with the indicated antibodies. (D) Reduced Mdm2 protein level in Csn6+/– MEFs. Endogenous Mdm2 was immunoprecipitated from primary MEFs, then probed with anti-Mdm2. Equal amounts of TCE were immunoblotted with the indicated antibodies. (E) Loss of Csn6 sensitized MEF cells to DOX-induced activation of p53. Primary MEFs from the same littermates were treated with and without DOX (1 μg/ml). Equal amounts of proteins from cell lysates were immunoblotted with the indicated antibodies. (F) Csn6 haploinsufficiency sensitized MEFs to DOX-induced apoptosis. Percent apoptotic population in each group was measured. P values were determined by 2-tailed t test.