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Progesterone Inhibits the Estrogen-Induced Phosphoinositide 3-KinaseAKTGSK-3ßCyclin D1pRB Pathway to Block Uterine Epithelial Cell Proliferation

Departments of Developmental and Molecular Biology and Obstetrics, Gynecology and Women’s Health, Center for the Study of Reproductive Biology and Women’s Health, Albert Einstein College of Medicine, New York, New York 10461

Address all correspondence and requests for reprints to: Jeffrey W. Pollard, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, New York 10461. E-mail: pollard{at}aecom.yu.edu

The mammalian cell cycle is regulated by the cyclin/cyclin-dependent kinase (CDK) phosphorylation of the retinoblastoma (pRB) family of proteins. Cyclin D1 with its CDK4/6 partners initiates the cell cycle and acts as the link between extracellular signals and the cell cycle machinery. Estradiol-17ß (E₂) stimulates uterine epithelial cell proliferation, a process that is completely inhibited by pretreatment with progesterone (P₄). Previously, we identified cyclin D1 localization as a key point of regulation in these cells with E₂ causing its nuclear accumulation and P₄ retaining it in the cytoplasm with the resultant inhibition of pRB phosphorylation. Here we show that E₂ stimulates phosphoinositide 3-kinase to activate phosphokinase B/AKT to effect an inhibitory phosphorylation of glycogen synthase kinase (GSK-3ß). This pathway is suppressed by P₄. Inhibition of the GSK-3ß activity in P₄-treated uteri by the specific inhibitor, LiCl, reversed the nuclear accumulation of cyclin D1 and in doing so, caused pRB phosphorylation and the induction of downstream genes, proliferating cell nuclear antigen and Ki67. Conversely, inhibition of phosphoinositide 3 kinase by LY294002 or Wortmanin reversed the E₂-induced GSK-3ß Ser⁹ inhibitory phosphorylation and blocked nuclear accumulation of cyclin D1. These data show the reciprocal actions of E₂ and P₄ on the phosphoinositide 3-kinase through to the GSK-3ß pathway that in turn regulates cyclin D1 localization and cell cycle progression. These data reveal a novel signaling pathway that links E₂ and P₄ action to growth factor-mediated signaling in the uterus.

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