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Molecular and Cellular Biology, September 2003, p. 6139-6149, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6139-6149.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

PTEN Induces Cell Cycle Arrest by Decreasing the Level and Nuclear Localization of Cyclin D1

Aurelian Radu,1 Valerie Neubauer,2 Tsuyoshi Akagi,3 Hidesaburo Hanafusa,3 and Maria-Magdalena Georgescu2,4*

Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York,1 Department of Neuro-Oncology,2 Department of Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas,4 Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan3

Received 12 November 2002/ Returned for modification 19 December 2002/ Accepted 2 June 2003

PTEN is a tumor suppressor frequently inactivated in brain, prostate, and uterine cancers that acts as a phosphatase on phosphatidylinositol-3,4,5-trisphosphate, antagonizing the activity of the phosphatidylinositol 3'-OH kinase. PTEN manifests its tumor suppressor function in most tumor cells by inducing G1-phase cell cycle arrest. To study the mechanism of cell cycle arrest, we established a tetracycline-inducible expression system for PTEN in cell lines lacking this gene. Expression of wild-type PTEN but not of mutant forms unable to dephosphorylate phosphoinositides reduced the expression of cyclin D1. Cyclin D1 reduction was accompanied by a marked decrease in endogenous retinoblastoma (Rb) protein phosphorylation on cyclin D/CDK4-specific sites, showing an early negative effect of PTEN on Rb inactivation. PTEN expression also prevented cyclin D1 from localizing to the nucleus during the G1- to S-phase cell cycle transition. The PTEN-induced localization defect and the cell growth arrest could be rescued by the expression of a nucleus-persistent mutant form of cyclin D1, indicating that an important effect of PTEN is at the level of nuclear availability of cyclin D1. Constitutively active Akt/PKB kinase counteracted the effect of PTEN on cyclin D1 translocation. The data are consistent with an oncogenesis model in which a lack of PTEN fuels the cell cycle by increasing the nuclear availability of cyclin D1 through the Akt/PKB pathway.

* Corresponding author. Mailing address: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 316, Houston, TX 77030-4095. Phone: (713) 792-4150. Fax: (713) 745-1183. E-mail: mgeorges{at}mdanderson.org.

Molecular and Cellular Biology, September 2003, p. 6139-6149, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.6139-6149.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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