Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers
Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers
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DOI：
10.1172/jci44111
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发表时间：
2011-03-01
影响因子：
15.9
通讯作者：
Lee, Mong-Hong
中科院分区：
文献类型：
--
作者：
Zhao, Ruiying;Yeung, Sai-Ching J.;Lee, Mong-Hong
哺乳动物组成型光形态发生9（COP 9）信号体（CSN）是一种参与胚胎发育的蛋白质复合物，参与细胞周期调控和DNA损伤反应。然而，它在肿瘤发展中的作用仍不清楚。在这里，我们已经表明，COP 9亚基6（CSN 6）基因在人类乳腺癌标本中扩增，CSN 6蛋白在人类乳腺癌和甲状腺肿瘤中上调。CSN 6表达与小鼠双微体2（MDM 2）的表达呈正相关，MDM 2是p53肿瘤抑制因子的有效负调节因子。CSN 6的表达似乎阻止了MDM 2在赖氨酸364处的自泛素化，导致MDM 2的稳定和p53的降解。缺失Csn 6的小鼠在胚胎发生早期死亡（E7.5）。缺乏Csn 6和p53的胚胎存活到胚胎发育后期（E10.5），这表明p53的缺失可以部分挽救Csn 6缺失的影响。Csn 6杂合子小鼠在胸腺和发育中的CNS中对γ辐射诱导的p53依赖性细胞凋亡敏感。这些小鼠对γ辐射诱导的肿瘤发生的敏感性也低于野生型小鼠。这些结果表明，CSN 6的损失增强p53介导的肿瘤抑制在体内和CSN 6通过控制MDM 2-p53信号通路在调节DNA损伤相关的细胞凋亡和肿瘤发生中起重要作用。
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 gamma-irradiation-induced, p53-dependent apoptosis in both the thymus and the developing CNS These mice were also less susceptible than wild-type mice to gamma-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.