TITLE

Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer

AUTHOR(S)

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

PUB. DATE

October 2002

SOURCE

Nature Medicine;Oct2002, Vol. 8 Issue 10, p1136

SOURCE TYPE

Academic Journal

DOC. TYPE

Article

ABSTRACT

The cyclin-dependent kinase inhibitor p27[sup kip1] is a putative tumor suppressor for human cancer. The mechanism underlying p27[sup kip1] 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 p27[sup kip1]-mediated growth arrest. Threonine 157 (T157), which maps within the nuclear localization signal of p27[sup kip1], is a predicted Akt-phosphorylation site. Akt-induced T157 phosphorylation causes retention of p27[sup kip1] in the cytoplasm, precluding p27[sup kip1]-induced G1 arrest. Conversely, the p27[sup kip1]-T157A mutant accumulates in cell nuclei and Akt does not affect p27[sup kip1]-T157A-mediated cell cycle arrest. Lastly, T157-phosphorylated p27[sup kip1] accumulates in the cytoplasm of primary human breast cancer cells coincident with Akt activation. Thus, cytoplasmic relocalization of p27[sup kip1], secondary to Akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27[sup kip1] are functionally inactivated and the proliferation of breast cancer cells is sustained.

ACCESSION #

7502779

Tags: CYCLIN-dependent kinases;  ANTIONCOGENES

 

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