Extra-Nuclear Signaling Pathway Involved in Progesterone-Induced Up-Regulations of p21(cip1) and p27(kip1) in Male Rat Aortic Smooth Muscle Cells

Previously, we demonstrated that progesterone (P4) at physiologic levels (5-500 nM) inhibited proliferation in cultured rat aortic smooth muscle cells (RASMCs) through a P4 receptor (PR)-dependent pathway. We also showed that P4-induced cell cycle arrest in RASMCs occurs when the cyclin-CDK2 system is inhibited just as p21(cip1) and p27(kip1) protein levels are augmented. In the present study, we further investigated the molecular mechanism underlying P4-induced up-regulations of p21(cip1) and p27(kip1) in RASMCs. We used pharmacological inhibitors as well as dominant negative constructs and conducted Western blot analyses to delineate the signaling pathway involved. Our data suggest that P4 up-regulated the expression of p21(cip1) and p27(kip1) in RASMCs through increasing the level of p53 protein mediated by activating the cSrc/Kras/Raf-1/AKT/ERK/p38/IκBα/NFκB pathway. The findings of the present study highlight the molecular mechanism underlying P4-induced up-regulations in p21(cip1) and p27(kip1) in RASMCs.