ERK-regulated early transcription factors and Cdc2 mediate progestin-induced proliferation of endometrial stroma

SARAGÜETA, PATRICIA

San Francisco

Simposio; The Endocrine Society´s 95th annual meeting & expo; 2013

The Endocrine Society

Speaker: Patricia Saragueta (patriciasaragueta2@gmail.com) 4:30 PM S61-2 - ERK-Regulated Early Transcription Factors and Cdc2 Mediate Progestin-Induced Proliferation of Endometrial Stroma Talk Description: Progesterone controls proliferation of rat endometrial stromal cells during the peri-implantation phase of pregnancy. Picomolar concentration of progestin R5020 mimics this control in UIII endometrial stromal cells via ERK1-2 and AKT activation mediated by interaction of Progesterone Receptor (PR) with Estrogen Receptor beta (ERβ). Here we identify early downstream targets of PR pathway and their possible role in physiological decidual proliferation. Microarray analysis of global gene expression changes in UIII cells treated for 45 min with progestin identified 97 up- and 341 down-regulated genes. The most over-represented molecular functions were transcription factors associated with cell proliferation. Further analysis showed that PR regulates Ccnd1, JunD, Usf1, Gfi1, Cyr61, and Cdkn1b through R5020 activation of ligand-free ER, ERK1-2 or AKT. The induction of the transcription factor USF1 and of its target CDC2 were validated at the protein level. USF1 ChIP experiments show that progestin-promoted interaction between USF1 and the proximal promoter of its target Ccd2 could directly regulate the expression of this cell cycle kinase. Moreover, Cdc2 knockdown blocked R5020 induced UIII cell proliferation. On the other hand, in 8 days pregnant rats CDC2 increased in antimesometrial decidua in association with activated ERK1-2 and PR. We conclude that progestin induced proliferation of endometrial stromal cells requires ERK1-2 mediated regulation of early transcription factors targeting the cell cycle gene Cdc2.