CDK inhibitor p57Kip2 is downregulated by Akt during HER2-mediated tumorigenicity
CDK inhibitor p57Kip2 is downregulated by Akt during HER2-mediated tumorigenicity
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DOI：
10.4161/cc.23883
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发表时间：
2013-03-15
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：
Zhao, Ruiying;Yang, Heng-Yin;Lee, Mong-Hong
HER 2/neu癌基因在肿瘤中经常发生失调，（PI 3 K）-Akt信号通路是介导HER 2/neu癌基因信号的主要通路之一。p57（Kip 2）是细胞周期蛋白依赖性激酶的抑制剂，在细胞周期调控中起着关键作用，但其上游调控因子尚不清楚。在这里，我们表明HER 2-Akt轴与p57（Kip 2）调节有关，Akt是p57（Kip 2）的负调节因子。Akt的异位表达可以降低p57（Kip 2）的表达，而Akt抑制则导致p57（Kip 2）的稳定。机制研究表明Akt与p57（Kip 2）相互作用并导致p57（Kip 2）的细胞质定位。Akt磷酸化位于Ser 282或Thr 310上的p57。Akt活性通过加速p57的周转速率和增强p57的泛素化而导致p57的不稳定。重要的是，HER 2/Akt对p57稳定性的负面影响有助于HER 2介导的细胞增殖、转化活性和致瘤性。p57修复可以减弱由HER 2引起的这些缺陷。值得注意的是，肿瘤样本的Kaplan-Meier分析表明，在观察到HER 2表达的肿瘤中，p57（Kip 2）的高表达水平与更好的总生存期相关。这些数据表明，HER 2/Akt是p57（Kip 2）的重要负调节因子，并且HER 2过表达细胞中p57的恢复可以减少乳腺肿瘤的生长。我们的研究结果表明，采用p57调节作为HER 2过表达癌症的治疗干预的适用性。
HER2/neu oncogene is frequently deregulated in cancers, and the (PI3K)-Akt signaling is one of the major pathways in mediating HER2/neu oncogenic signal. p57(Kip2), an inhibitor of cyclin-depependent kinases, is pivotal in regulating cell cycle progression, but its upstream regulators remain unclear. Here we show that the HER2-Akt axis is linked to p57(Kip2) regulation, and that Akt is a negative regulator of p57(Kip2). Ectopic expression of Akt can decrease the expression of p57(Kip2), while Akt inhibition leads to p57(Kip2) stabilization. Mechanistic studies show that Akt interacts with p57(Kip2) and causes cytoplasmic localization of p57(Kip2). Akt phosphorylates p57 on Ser 282 or Thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination. Importantly, the negative impact of HER2/Akt on p57 stability contributes to HER2-mediated cell proliferation, transformational activity and tumorigenicity. p57 restoration can attenuate these defects caused by HER2. Significantly, Kaplan-Meier analysis of tumor samples demonstrate that in tumors where HER2 expression was observed, high expression levels of p57(Kip2) were associated with better overall survival. These data suggest that HER2/Akt is an important negative regulator of p57(Kip2), and that p57 restoration in HER2-overexpressing cells can reduce breast tumor growth. Our findings indicate the applicability of employing p57 regulation as a therapeutic intervention in HER2-overexpressing cancers.