The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation.
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.
Chung
Ji-Hyun
JH
Human Cancer Genetics Program, Comprehensive Cancer Center, Department of Molecular and Cellular Biochemistry, Division of Human Genetics, The Ohio State University, Columbus, USA.
Ostrowski
Michael C
MC
Romigh
Todd
T
Minaguchi
Takeo
T
Waite
Kristin A
KA
Eng
Charis
C
D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction; D013489:Suppression, Genetic; D014158:Transcription, Genetic; D014162:Transfection
D019913:Nuclear Localization Signals; D019938:Cyclin D1; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human