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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Amino Acid Motifs
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Blotting, Western
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Cell Division / genetics
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Cell Division / physiology*
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Cell Fractionation
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Cell Line
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / genetics
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Cyclins / metabolism*
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Cytoplasm / metabolism*
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Enzyme Inhibitors / metabolism*
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Female
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Fibroblasts
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Gene Expression Regulation
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Mice
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Microscopy, Fluorescence
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Protein Transport
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism*
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Signal Transduction / physiology
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Transfection
Substances
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Antigens, Neoplasm
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Enzyme Inhibitors
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Proto-Oncogene Proteins
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Receptor, ErbB-2
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt