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

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

Authors

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

Journal

Nature cell biology

Publication Data

March 20, 2001

Associated Grants

None

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