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

B P Zhou; Y Liao; W Xia; B Spohn; M H Lee; M C Hung

doi:10.1038/35060032

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.

Authors

B P Zhou¹, Y Liao, W Xia, B Spohn, M H Lee, M C Hung

Affiliation

¹ Department of Molecular and Cellular Oncology, Breast Cancer Basic Research Program, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

PMID: 11231573
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 Serine-Threonine Kinases*
Protein Transport
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