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Nuclear-Cytoplasmic Partitioning of Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Differentially Regulates the Cell Cycle and Apoptosis

¹ Clinical Cancer Genetics Program, Human Cancer Genetics Program, Comprehensive Cancer Center; ² Department of Molecular Virology, Immunology and Medical Genetics; and ³ Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus, Ohio; ⁴ Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute; ⁵ Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio; and ⁶ Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge, United Kingdom

Requests for reprints: Charis Eng, Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Mailstop NE-30 (NE-50 after January 2006), Cleveland, OH 44195. Phone: 216-444-3440; Fax: 216-636-0655; E-mail: engc{at}ccf.org.

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a tumor suppressor phosphatase that dephosphorylates both protein and lipid substrates, is found to be mutated in both heritable and sporadic breast cancer. Cellular PTEN has been shown to regulate Akt phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, p27^kip1, and cyclin D1 protein levels. Additionally, we and others have shown that PTEN can regulate not only the cell cycle but also cellular apoptosis. Until recently, the functions of PTEN have been thought to occur through cytoplasmic PTEN. However, we have shown that PTEN localizes to the nucleus and that this localization coincides with the G₀-G₁ phases of the cell cycle. Furthermore, we have shown that PTEN has bipartite nuclear localization sequence (NLS)-like sequences that are required for major vault protein-mediated nuclear import. These findings suggest that subcellular localization of PTEN may regulate its function and that nuclear-localized PTEN may regulate unique cellular functions that have been attributed to cytoplasmic PTEN. To examine this possibility, we analyzed downstream PTEN readouts using MCF-7 Tet-Off breast cancer cell lines stably transfected with two different NLS mutant PTEN constructs, which do not localize to the nucleus, and compared these with cells transfected with wild-type PTEN and empty vector control cells. We found that cytoplasmic PTEN down-regulates phosphorylation of Akt and up-regulates p27^kip1, whereas nuclear PTEN down-regulates cyclin D1 and prevents the phosphorylation of MAPK. Additionally, whereas we observe that nuclear PTEN is required for cell cycle arrest, we found that cytoplasmic PTEN is required for apoptosis. Our observations show that nuclear-cytoplasmic partitioning differentially regulates the cell cycle and apoptosis and, in this manner, provide further evidence that nuclear import of PTEN should play a role in carcinogenesis.

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