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 G(0)-G(1) 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.