Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27kip1 by PKB/Akt-mediated phosphorylation in breast cancer

Giuseppe Viglietto, Maria Letizia Motti, Paola Bruni, Rosa Marina Melillo, Amelia D'Alessio, Daniela Califano, Floriana Vinci, Gennaro Chiappetta, Philip Tsichliss, Alfonso Bellacosa, Alfredo Fusco, Massimo Santoro

Research output: Contribution to journalArticlepeer-review

Abstract

The cyclin-dependent kinase inhibitor p27kip1 is a putative tumor suppressor for human cancer. The mechanism underlying p27kip1 deregulation in human cancer is, however, poorly understood. We demonstrate that the serine/threonine kinase Akt regulates cell proliferation in breast cancer cells by preventing p27kip1-mediated growth arrest. Threonine 157 (T157), which maps within the nuclear localization signal of p27kip1, is a predicted Akt-phosphorylation site. Akt-induced T157 phosphorylation causes retention of p27kip1 in the cytoplasm, precluding p27kip1-induced G1 arrest. Conversely, the p27kip1-T157A mutant accumulates in cell nuclei and Akt does not affect p27kip1-T157A-mediated cell cycle arrest. Lastly, T157-phosphorylated p27kip1 accumulates in the cytoplasm of primary human breast cancer cells coincident with Akt activation. Thus, cytoplasmic relocalization of p27kip1, secondary to Akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27kip1 are functionally inactivated and the proliferation of breast cancer cells is sustained.

Original languageEnglish
Pages (from-to)1136-1144
Number of pages9
JournalNature Medicine
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 1 2002

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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