Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.

Abstract

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

• Authors: Giuseppe Viglietto, Maria Letizia Motti, Paola Bruni, Rosa Marina Melillo, Amelia D'Alessio, Daniela Califano, Floriana Vinci, Gennaro Chiappetta, Philip Tsichlis, Alfonso Bellacosa, Alfredo Fusco, Massimo Santoro
• Journal: Nature medicine (Nat Med) Vol. 8 Issue 10 Pg. 1136-44 (Oct 2002) ISSN: 1078-8956 [Print] United States
• PMID: 12244303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Enzyme Inhibitors
• Proto-Oncogene Proteins
• Tumor Suppressor Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• Threonine
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Cyclin-Dependent Kinases

Topics

• Breast Neoplasms (metabolism, pathology)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line
• Cell Nucleus (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Enzyme Inhibitors (metabolism)
• Female
• Genes, Tumor Suppressor
• Humans
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Threonine (metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)