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.
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We thank D. Yu, R. B. Arlinghaus and W. H. Klein for critical comments on the manuscript. This work was supported by grants from the National Institutes of Health (to M-C.H.), by a SPORE grant in ovarian cancer (to M-C.H.), and by the Nellie Connally Breast Cancer Research Fund at the M. D. Anderson Cancer Center (M-C.H.). B.P.Z. is a recipient of a postdoctoral fellowship from the US Department of Defense Breast Cancer Research.
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