Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers
Ruiying Zhao, … , Guillermina Lozano, Mong-Hong Lee
Ruiying Zhao, … , Guillermina Lozano, Mong-Hong Lee
Published February 7, 2011
Citation Information: J Clin Invest. 2011;121(3):851-865. https://doi.org/10.1172/JCI44111.
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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 1

Amplification of CSN6 gene copy number in human breast cancers.

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Amplification of CSN6 gene copy number in human breast cancers. (A) ...
(A) SIGMA analysis of the CSN6 gene loci was performed on a CGH data set of BCCRC SMRT arrays. 100%, gain of that locus in all samples; –100%, loss of that locus in all samples. (B) Regions of gains and loss (at 0.9 megabase resolution) across chromosome 7 in a set of 47 primary breast cancer samples and 18 breast cancer cell lines are shown. Figure adapted from Breast Cancer Research (31). Red, recurrent loss, green, recurrent gain. (C) CSN6 gene copies were assessed in a cohort of 58 primary human breast cancer genomic DNA samples, and the frequency of human breast cancer samples with or without CSN6 gene amplification is shown. (D) Amplification of the CSN6 gene was associated with tumor size larger than 8 cm3 at the time of surgical resection in the cohort examined in C. Bounds of the boxes denote interquartile range; solid and dashed lines denote median and mean, respectively; whiskers denote 90% and 10%; symbols denote outliers. (E) Hierarchical clustering was performed on the cohort examined in C with the indicated pathological and genomic markers; data are presented as a heat map.