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Institute of Physiology, School of Medicine, National Yang-Ming University, 155 Linong Street, Section 2, Taipei 112, Taiwan, Republic of China
¹ Agricultural Biotechnology Research Center,
² Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan, Republic of China
³ Division of Reproductive and Developmental Science, Queen’s Medical Research Institute, Edinburgh University, Edinburgh EH16 4TJ, UK
⁴ Institute of Molecular and Cellular Biology, School of Life Science, National Taiwan University, Taipei 106, Taiwan, ROC

(Requests for offprints should be addressed to F-C Ke; Email: fck{at}ccms.ntu.edu.tw; or to J-J Hwang; Email: jiuanh{at}ym.edu.tw)

Transforming growth factor (TGF) ß1 facilitates FSH-induced differentiation of rat ovarian granulosa cells. The signaling crosstalk between follicle stimulating hormone (FSH) and TGFß receptors remains unclear. This study was to investigate the interplay of cAMP/protein kinase A (PKA) and phosphatidylinositol-3-kinase (PI3K) signaling including mammalian target of rapamycin (mTOR)C1 dependence in FSH- and TGFß1-stimulated steroidogenesis in rat granulosa cells. To achieve this aim, inhibitors of PKA (PKAI), PI3K (wortmannin), and mTORC1 (rapamycin) were employed. PKAI and wortmannin suppressions of the FSH-increased progesterone production were partly attributed to decreased level of 3ß-HSD, and their suppression of the FSH plus TGFß1 effect was attributed to the reduction of all the three key players, steroidogenic acute regulatory (StAR) protein, P450scc, and 3ß-HSD. Further, FSH activated the PI3K pathway including increased integrin-linked kinase (ILK) activity and phosphorylation of Akt(S473), mTOR(S2481), S6K(T389), and transcription factors particularly FoxO1(S256) and FoxO3a(S253), which were reduced by wortmannin treatment but not by PKAI. Interestingly, PKAI suppression of FSH-induced phosphorylation of cAMP regulatory element-binding protein (CREB(S133)) disappeared in the presence of wortmannin, suggesting that wortmannin may affect intracellular compartmentalization of signaling molecule(s).

In addition, TGFß1 had no effect on FSH-activated CREB and PI3K signaling mediators. We further found that rapamycin reduced the TGFß1-enhancing effect of FSH-stimulated steroidogenesis, yet it exhibited no effect on FSH action. Surprisingly, rapamycin displayed a suppressive effect at concentrations that had no effect on mTORC1 activity. Together, this study demonstrates a delicate interplay between cAMP/PKA and PI3K signaling in FSH and TGFß1 regulation of steroidogenesis in rat granulosa cells. Furthermore, we demonstrate for the first time that TGFß1 acts in a rapamycin-hypersensitive and mTORC1-independent manner in augmenting FSH-stimulated steroidogenesis in rat granulosa cells.

This article has been cited by other articles:

				Y.-J. Chen, M.-T. Lee, H.-C. Yao, P.-W. Hsiao, F.-C. Ke, and J.-J. Hwang Crucial Role of Estrogen Receptor-{alpha} Interaction with Transcription Coregulators in Follicle-Stimulating Hormone and Transforming Growth Factor {beta}1 Up-Regulation of Steroidogenesis in Rat Ovarian Granulosa Cells Endocrinology, September 1, 2008; 149(9): 4658 - 4668. [Abstract] [Full Text] [PDF]