Nat Cell Biol. 2001 Mar;3(3):245-52.

Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells.

Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC.

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Department of Molecular and Cellular Oncology, Breast Cancer Basic Research Program, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

Amplification or overexpression of HER-2/neu in cancer cells confers resistance to apoptosis and promotes cell growth. The cellular localization of p21Cip1/WAF1 has been proposed to be critical either in promoting cell survival or in inhibiting cell growth. Here we show that HER-2/neu-mediated cell growth requires the activation of Akt, which associates with p21Cip1/WAF1 and phosphorylates it at threonine 145, resulting in cytoplasmic localization of p21Cip1/WAF1. Furthermore, blocking the Akt pathway with a dominant-negative Akt mutant restores the nuclear localization and cell-growth-inhibiting activity of p21Cip1/WAF1. Our results indicate that HER-2/neu induces cytoplasmic localization of p21Cip1/WAF1 through activation of Akt to promote cell growth, which may have implications for the oncogenic activity of HER-2/neu and Akt.

Comment in

Nat Cell Biol. 2001 Mar;3(3):E71-3.

PMID:: 11231573; [PubMed - indexed for MEDLINE]

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