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首页> 外文期刊>Cell cycle >CDK inhibitor p57Kip2 is downregulated by Akt during HER2-mediated tumorigenicity
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CDK inhibitor p57Kip2 is downregulated by Akt during HER2-mediated tumorigenicity

机译：CDK抑制剂p57Kip2在HER2介导的致瘤性过程中被Akt下调

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HER2eu oncogene is frequently deregulated in cancers, and the (PI3K)-Akt signaling is one of the major pathways in mediating HER2eu oncogenic signal. p57Kip2, 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 p57Kip2 regulation, and that Akt is a negative regulator of p57Kip2. Ectopic expression of Akt can decrease the expression of p57Kip2, while Akt inhibition leads to p57Kip2 stabilization. Mechanistic studies show that Akt interacts with p57Kip2 and causes cytoplasmic localization of p57Kip2. 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 p57Kip2 were associated with better overall survival. These data suggest that HER2/Akt is an important negative regulator of p57Kip2, 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.
机译：HER2 / neu癌基因在癌症中经常失调，（PI3K）-Akt信号传导是介导HER2 / neu致癌信号的主要途径之一。 p57Kip2是细胞周期蛋白依赖性激酶的抑制剂，在调节细胞周期进程中起着关键作用，但其上游调节剂仍不清楚。在这里，我们显示HER2-Akt轴与p57Kip2调节相关，而Akt是p57Kip2的负调节剂。 Akt的异位表达可以降低p57Kip2的表达，而Akt的抑制导致p57Kip2的稳定。机理研究表明，Akt与p57Kip2相互作用并引起p57Kip2的胞质定位。 Akt使Ser 282或Thr310上的p57磷酸化。 Akt活性通过加速p57的周转率和增强p57泛素化而导致p57不稳定。重要的是，HER2 / Akt对p57稳定性的负面影响有助于HER2介导的细胞增殖，转化活性和致瘤性。 p57修复可以减轻由HER2引起的这些缺陷。重要的是，对肿瘤样品的Kaplan-Meier分析表明，在观察到HER2表达的肿瘤中，p57Kip2的高表达水平与更好的总体存活率有关。这些数据表明，HER2 / Akt是p57Kip2的重要负调节剂，HER2过表达细胞中的p57还原可减少乳腺肿瘤的生长。我们的发现表明，在过度表达HER2的癌症中采用p57调控作为治疗干预措施的适用性。

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