Human Molecular Genetics Advance Access originally published online on July 18, 2006
Human Molecular Genetics 2006 15(17):2553-2559; doi:10.1093/hmg/ddl177
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The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation
1 Human Cancer Genetics Program, Comprehensive Cancer Center, 2 Department of Molecular and Cellular Biochemistry and 3 Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA, 4 Genomic Medicine Institute, 5 Lerner Research Institute and 6 Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA, 7 Department of Genetics and 8 CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
* To whom correspondence should be addressed: Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Mailstop NE-50 Cleveland, OH 44195, USA. Tel: +1 2164443440; Fax: +1 2166360655; Email: engc{at}ccf.org
Received December 19, 2005; Revised June 24, 2006; Accepted July 7, 2006
PTEN, a tumor suppressor phosphatase that dephosphorylates both protein and lipid substrates, is mutated in both heritable and sporadic breast cancer. Until recently, PTEN-mediated cell cycle arrest and apoptosis were thought to occur through its well-documented cytoplasmic activities. We have shown that PTEN localizes to the nucleus coincident with the G0–G1 phases of the cell cycle and that compartmentalization may regulate cell cycle progression dependent upon the down-regulation of cyclin D1. However, the mechanism for cyclin D1-dependent growth suppression by nuclear PTEN has remained largely undefined. Utilizing MCF-7 Tet-Off breast cancer cell lines stably expressing two different nuclear localization defective PTEN mutants, as well as wild-type PTEN and empty vector control cells, we demonstrate that nuclear PTEN down-regulates cyclin D1 transcription and this event is mediated by the down-regulation of MAPK specifically by nuclear localized PTEN. These results provide further evidence that nuclear PTEN plays a role through cell cycle suppression functions in regulating carcinogenesis.
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