CDK inhibitor p57Kip2 is negatively regulated by COP9 signalosome subunit 6
CDK inhibitor p57Kip2 is negatively regulated by COP9 signalosome subunit 6
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CDK 抑制剂 p57Kip2 受 COP9 信号体亚基 6 负调节
DOI：
10.4161/cc.22887
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发表时间：
2012-12-15
期刊：
影响因子：
4.3
通讯作者：
Lee, Mong-Hong
中科院分区：
文献类型：
--
作者：
Chen, Bo;Zhao, Ruiying;Lee, Mong-Hong
已知COP 9信号体复合物CSN 6的亚基6对调节MDM 2-p53轴以实现细胞增殖和抗凋亡至关重要，但其许多靶点仍不清楚。在这里，我们表明p57 Kip 2是CSN 6的靶点，而CSN 6是p57 Kip 2的负调节因子。CSN 6与p57 Kip 2相关，其过表达可降低p57 Kip 2的稳态表达，因此CSN 6缺陷导致p57 Kip 2稳定。机制研究表明，CSN 6与p57 Kip 2和Skp 2（E3连接酶的一种组分）相关联，这反过来又促进Skp 2介导的p57 Kip 2蛋白泛素化。Skp 2的缺失损害了CSN 6介导的p57 Kip 2不稳定，表明Skp 2和CSN 6在p57 Kip 2降解中的协作。CSN 6对p57 Kip 2升高的负面影响转化为细胞生长促进、细胞周期失调和增强的转化活性。值得注意的是，肿瘤样本的单变量Kaplan-Meier分析表明，高CSN 6表达或低p57表达与较差的总体存活率相关。这些数据表明，CSN 6是p57 Kip 2的重要负调节因子，并且在许多类型的癌症中CSN 6的过表达可导致p57 Kip 2表达降低并导致促进癌细胞生长。
Subunit 6 of the COP9 signalosome complex, CSN6, is known to be critical to the regulation of the MDM2-p53 axis for cell proliferation and anti-apoptosis, but its many targets remain unclear. Here we show that p57Kip2 is a target of CSN6, and that CSN6 is a negative regulator of p57Kip2. CSN6 associates with p57Kip2, and its overexpression can decrease the steady-state expression of p57Kip2; accordingly, CSN6 deficiency leads to p57Kip2 stabilization. Mechanistic studies show that CSN6 associates with p57Kip2 and Skp2, a component of the E3 ligase, which, in turn, facilitates Skp2-mediated protein ubiquitination of p57Kip2. Loss of Skp2 compromised CSN6-mediated p57Kip2 destabilization, suggesting collaboration between Skp2 and CSN6 in degradation of p57Kip2. CSN6’s negative impact on p57Kip2 elevation translates into cell growth promotion, cell cycle deregulation and potentiated transformational activity. Significantly, univariate Kaplan-Meier analysis of tumor samples demonstrates that high CSN6 expression or low p57 expression is associated with poor overall survival. These data suggest that CSN6 is an important negative regulator of p57Kip2, and that overexpression of CSN6 in many types of cancer could lead to decreased expression of p57Kip2 and result in promoted cancer cell growth.