CDK inhibitor p57Kip2 is downregulated by Akt during HER2-mediated tumorigenicity

• DOI: 10.4161/cc.23883
• Publication Date: 2013-03-13T16:07:37Z
• Authors: Ruiying Zhao; Heng-Yin Yang; Jihyun Shin; Liem Phan; Lekun Fang; Ting-Fang Che; Chun-Hui Su; Sai-Ching J. Yeung; Mong-Hong Lee
• Keywords: Ectopic expression

HER2/neu oncogene is frequently deregulated in cancers, and the (PI3K)-Akt signaling one of major pathways mediating oncogenic signal. p57Kip2, an inhibitor cyclin-depependent kinases, pivotal regulating cell cycle progression, but its upstream regulators remain unclear. Here we show that HER2-Akt axis linked to p57Kip2 regulation, Akt a negative regulator p57Kip2. Ectopic expression can decrease while inhibition leads stabilization. Mechanistic studies interacts with causes cytoplasmic localization phosphorylates p57 on Ser 282 or Thr310. activity results destabilization by accelerating turnover rate enhancing ubiquitination. Importantly, impact HER2/Akt stability contributes HER2-mediated proliferation, transformational tumorigenicity. restoration attenuate these defects caused HER2. Significantly, Kaplan-Meier analysis tumor samples demonstrate tumors where HER2 was observed, high levels were associated better overall survival. These data suggest important HER2-overexpressing cells reduce breast growth. Our findings indicate applicability employing regulation as therapeutic intervention cancers.