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

Nature cell biology | Mar 20, 2001

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.

Pubmed ID: 11231573 RIS Download

Mesh terms: 3T3 Cells | Adenocarcinoma | Amino Acid Motifs | Animals | Antigens, Neoplasm | Blotting, Western | Breast Neoplasms | Cell Division | Cell Fractionation | Cell Line | Cyclin-Dependent Kinase Inhibitor p21 | Cyclins | Cytoplasm | Enzyme Inhibitors | Female | Fibroblasts | Gene Expression Regulation | Mice | Microscopy, Fluorescence | Phosphorylation | Protein Transport | Protein-Serine-Threonine Kinases | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-akt | Receptor, ErbB-2 | Signal Transduction | Transfection

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