Submission Number: ABR-4-31-5

Abstract Number: 34

INVOLVEMENT OF MAPK IN DESENSITIZATION TO GONADOTROPIN HORMONE IN GRANULOSA CELLS IS IMPLICATED WITH DOWN-REGULATION OF THE STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR).

Abraham Amsterdam* ¹, Revital Rosenberg ¹, Ada Dantes ¹, Kimihisa Tajima ¹, Tammy Hanoch ², JF Strauss III* ³ and Ronny Seger ²

Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel ¹
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel ²
Center for Research on Reproduction and Woman's Health, University of Pennsylvania Medical Center, Philadelphia, PA ³

Abstract:
Gonadotropic hormones LH/CG and FSH exert their effects on follicular ovarian cells (granulosa cells) via binding to specific heptohelical receptors which leads to activation of adenylate cyclase and induction of steroidogenesis. Massive stimulation (e.g. high dose of hormone for prolonged time) leads to desensitization. We suggested that phosphorylation and clustering of the receptor molecules rather than internalization can explain this phenomena. In this work LH/CG or FSH stimulation of both primary and human granulosa cell lines established in our laboratory resulted in transient activation of the MAPKs ERK1 and ERK2. To study the physiological role of ERKs activation we used specific MEK inhibitors (UO126 and PD 98059) which drastically reduced ERKs activation by LH/CG and FSH . These inhibitors when coincubated with gonadotropins abolished desensitization and enhanced 3-7 fold the gonadotropin-induced progesterone production. Moreover, incubation of the cells with the inhibitors sharply increased the levels of the recently discovered steroidogenic acute regulatory protein (StAR). This was verified both by Western blot and Immunofluorecence labeling of the treated granulosa cells using a specific StAR antibodies. We suggest that cross-talk between MAPK activation and steroidogenic factors can attenuate the steroidogenic response to gonadotropins and thus may explain the phenomenon of desensitization. In future experiments we shall test the hypothesis that gonadotropins induce on the one hand signals for differentiation, mediated by activation of adenylate cyclase, and on the other hand signals for survival and proliferation of the cells, mediated by the activation of ERKs. .

Keywords: Gonadotropins, MAPK , StAR, Granulosa

This abstract is being presented at: 4:15 PM in session:
SESSION 5: SIGNAL TRANSDUCTION IN REPRODUCTIVE TISSUES