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Crucial Role of Estrogen Receptor- Interaction with Transcription Coregulators in Follicle-Stimulating Hormone and Transforming Growth Factor β1 Up-Regulation of Steroidogenesis in Rat Ovarian Granulosa Cells

Institute of Physiology, School of Medicine (Y.-J.C., H.-C.Y., J.-J.H.), National Yang-Ming University, Taipei 112, Taiwan; Institutes of Biological Chemistry (M.-T.L.) and BioAgricultural Sciences (P.-W.H.), Academia Sinica, Taipei 115, Taiwan; and Institute of Molecular and Cellular Biology (F.-C.K.), School of Life Science, National Taiwan University, Taipei 106, Taiwan

Address all correspondence and requests for reprints to: Jiuan-Jiuan Hwang, Institute of Physiology, School of Medicine, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, Taiwan. E-mail: jiuanh{at}ym.edu.tw; or Ferng-Chun Ke, Institute of Molecular and Cellular Biology, School of Life Science, National Taiwan University, 1 Roosevelt Road, Section 4, Taipei 106, Taiwan. E-mail: fck{at}ccms.ntu.edu.tw.

This study was to explore estrogen receptor (ER) involvement in FSH and TGFβ1-stimulated steroidogenesis in rat ovarian granulosa cells. We first determined the specific involvement of ER and ERβ in the process, and then investigated the molecular interaction of ER and transcription coregulators in FSH and TGFβ1 up-regulation of steroidogenic gene expression. Primary culture of ovarian granulosa cells from antral follicles of gonadotropin-primed immature rats was used. Interestingly, a selective ER antagonist methyl-piperidino-pyrazole (MPP) [like ER antagonist ICI-182,780 (ICI)] decreased FSH ± TGFβ1-stimulated progesterone production, whereas an androgen receptor antagonist hydroxyflutamide and particularly a selective ERβ antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl) pyrazolo [1,5-a] pyrimidin-3-yl] phenol had no significant effect. Consistent with this, a selective ERβ agonist diarylpropionitrile (unlike 17β-estradiol) also had no effect on FSH ± TGFβ1-stimulated progesterone production. Furthermore, a selective ER agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (like 17β-estradiol) enhanced FSH-stimulated progesterone production, and this was abolished by pretreatment with MPP. Immunoblotting and chromatin immunoprecipitation analyses indicate that MPP/ICI suppression of FSH ± TGFβ1 action is partly attributed to the reduced ER-mediated expression of Hsd3b and Cyp11a1 genes, but not steroidogenic acute regulatory protein. Furthermore, FSH ± TGFβ1 increased ER association with histone acetylases (CBP and SRC-1) and coactivator of peroxisome proliferator-activated receptor (PGC-1), and MPP/ICI dramatically reduced these interactions. In addition, FSH ± TGFβ1 increased CBP, SRC-1, and PGC-1 binding to Hsd3b and Cyp11a1 genes. Together, we demonstrate for the first time that ER interaction with transcription coregulators, histone acetylases (CBP/SRC-1), and PGC-1 is crucial to FSH and TGFβ1-up-regulated expression of Hsd3b and Cyp11a1, and, thus, progesterone production in rat ovarian granulosa cells.

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				H. A. LaVoie and S. R. King Transcriptional Regulation of Steroidogenic Genes: STARD1, CYP11A1 and HSD3B Experimental Biology and Medicine, August 1, 2009; 234(8): 880 - 907. [Abstract] [Full Text] [PDF]