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

Nat Cell Biol. 2001 Mar;3(3):245-52. doi: 10.1038/35060032.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Antigens, Neoplasm
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Receptor, ErbB-2
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt