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J. Biol. Chem., Vol. 279, Issue 19, 19431-19440, May 7, 2004

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Follicle-stimulating Hormone Activation of Hypoxia-inducible Factor-1 by the Phosphatidylinositol 3-Kinase/AKT/Ras Homolog Enriched in Brain (Rheb)/Mammalian Target of Rapamycin (mTOR) Pathway Is Necessary for Induction of Select Protein Markers of Follicular Differentiation^*

Hena Alam, Evelyn T. Maizels, Youngkyu Park, Shail Ghaey, Zachary J. Feiger, Navdeep S. Chandel, and Mary Hunzicker-Dunn¶

From the Departments of Cell and Molecular Biology and Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611

We sought to elucidate the role of AKT in follicle-stimulating hormone (FSH)-mediated granulosa cell (GC) differentiation. Our results define a signaling pathway in GCs whereby the inactivating phosphorylation of tuberin downstream of phosphatidylinositol (PI) 3-kinase/AKT activity leads to Rheb (Ras homolog enriched in brain) and subsequent mTOR (mammalian target of rapamycin) activation. mTOR then stimulates translation by phosphorylating p70 S6 kinase and, consequently, the 40 S ribosomal protein S6. Activation of this pathway is required for FSH-mediated induction of several follicular differentiation markers, including luteinizing-hormone receptor (LHR), inhibin-, microtubule-associated protein 2D, and the PKA type II regulatory subunit. FSH also promotes activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). FSH-stimulated HIF-1 activity is inhibited by the PI 3-kinase inhibitor LY294002, the Rheb inhibitor FTI-277 (farnesyltransferase inhibitor-277), and the mTOR inhibitor rapamycin. Finally, we find that the FSH-mediated up-regulation of reporter activities for LHR, inhibin-, and vascular endothelial growth factor is dependent upon HIF-1 activity, because a dominant negative form of HIF-1 interferes with the up-regulation of these genes. These results show that FSH enhances HIF-1 activity downstream of the PI 3-kinase/AKT/Rheb/mTOR pathway in GCs and that HIF-1 activity is necessary for FSH to induce multiple follicular differentiation markers.

Received for publication, February 4, 2004 , and in revised form, February 20, 2004.

^* This work was supported by National Institutes of Health Grants PO1-HD-21921 (to M. H. D.), GM60472-05, and P01-HL071643, American Heart Association Grant 0350054N (to N. S. C.), and National Institutes of Health Training Program in Reproductive Biology Grant T32 HD 07086. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-8940; Fax: 312-503-0566; E-mail: mhd{at}northwestern.edu.

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