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CDK inhibitor p57 (Kip2) is downregulated by Akt during HER2-mediated tumorigenicity

Ruiying Zhao1, Heng-Yin Yang, Jihyun Shin

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cell Cycle (Georgetown, Tex.)
|February 21, 2013
PubMed

Insights

The HER2-Akt pathway negatively regulates p57 (Kip2) protein stability, promoting cancer growth. Restoring p57 (Kip2) can inhibit HER2-driven tumor progression and improve survival in HER2-overexpressing cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • HER2/neu oncogene deregulation is common in cancers.
  • The PI3K-Akt pathway mediates HER2/neu oncogenic signaling.
  • p57 (Kip2), a cell cycle inhibitor, has unclear upstream regulators.

Purpose of the Study:

  • To investigate the link between the HER2-Akt axis and p57 (Kip2) regulation.
  • To elucidate the role of Akt in controlling p57 (Kip2) expression and stability.
  • To determine the therapeutic potential of p57 (Kip2) restoration in HER2-overexpressing cancers.

Main Methods:

  • Investigated Akt's effect on p57 (Kip2) expression and stability via ectopic expression and inhibition.
  • Performed mechanistic studies including interaction, localization, and phosphorylation assays.
  • Analyzed tumor samples using Kaplan-Meier survival analysis.

Main Results:

  • Akt acts as a negative regulator of p57 (Kip2), decreasing its expression and promoting its destabilization through cytoplasmic localization and phosphorylation.
  • Akt activity accelerates p57 (Kip2) turnover and enhances its ubiquitination.
  • p57 (Kip2) restoration attenuated HER2-mediated cell proliferation, transformation, and tumorigenicity.
  • High p57 (Kip2) levels correlated with better survival in HER2-expressing tumors.

Conclusions:

  • The HER2-Akt pathway negatively regulates p57 (Kip2) stability, contributing to cancer progression.
  • Restoring p57 (Kip2) shows therapeutic potential in HER2-overexpressing cancers.
  • Targeting p57 (Kip2) regulation could be a viable therapeutic strategy for HER2-driven malignancies.
Keywords:
AktHER2cell cyclep57 Kip2phosphorylationsubcellular localizaiton

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