PMID- 14982927 OWN - NLM STAT- MEDLINE DCOM- 20040615 LR - 20211203 IS - 0021-9258 (Print) IS - 1083-351X (Electronic) IS - 0021-9258 (Linking) VI - 279 IP - 19 DP - 2004 May 7 TI - 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. PG - 19431-40 AB - 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-alpha, microtubule-associated protein 2D, and the PKA type IIbeta 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-alpha, and vascular endothelial growth factor is dependent upon HIF-1 activity, because a dominant negative form of HIF-1alpha 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. FAU - Alam, Hena AU - Alam H AD - Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. FAU - Maizels, Evelyn T AU - Maizels ET FAU - Park, Youngkyu AU - Park Y FAU - Ghaey, Shail AU - Ghaey S FAU - Feiger, Zachary J AU - Feiger ZJ FAU - Chandel, Navdeep S AU - Chandel NS FAU - Hunzicker-Dunn, Mary AU - Hunzicker-Dunn M LA - eng GR - P01 HD021921/HD/NICHD NIH HHS/United States GR - T32 HD 07086/HD/NICHD NIH HHS/United States GR - GM 60472-05/GM/NIGMS NIH HHS/United States GR - P01 HL071643/HL/NHLBI NIH HHS/United States GR - P01 HL 071643/HL/NHLBI NIH HHS/United States GR - P01 HD 21921/HD/NICHD NIH HHS/United States GR - R01 GM060472/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20040224 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Chromones) RN - 0 (Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit) RN - 0 (DNA-Binding Proteins) RN - 0 (Enzyme Inhibitors) RN - 0 (Hif1a protein, rat) RN - 0 (Hypoxia-Inducible Factor 1) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Morpholines) RN - 0 (Neuropeptides) RN - 0 (Nuclear Proteins) RN - 0 (Prkar2b protein, rat) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Ras Homolog Enriched in Brain Protein) RN - 0 (Receptors, LH) RN - 0 (Rheb protein, rat) RN - 0 (Transcription Factors) RN - 0 (inhibin-alpha subunit) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - 57285-09-3 (Inhibins) RN - 9002-68-0 (Follicle Stimulating Hormone) RN - EC 1.13.12.- (Luciferases) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Akt1 protein, rat) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) RN - EC 3.6.5.2 (Monomeric GTP-Binding Proteins) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Animals MH - Cell Differentiation MH - Chromones/pharmacology MH - Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit MH - Cyclic AMP-Dependent Protein Kinases/metabolism MH - DNA-Binding Proteins/*metabolism MH - Enzyme Activation MH - Enzyme Inhibitors/pharmacology MH - Female MH - Follicle Stimulating Hormone/*metabolism MH - Genes, Dominant MH - Genes, Reporter MH - Granulosa Cells/cytology MH - Hypoxia-Inducible Factor 1 MH - Hypoxia-Inducible Factor 1, alpha Subunit MH - Inhibins/metabolism MH - Luciferases/metabolism MH - Microtubule-Associated Proteins/metabolism MH - Models, Biological MH - Monomeric GTP-Binding Proteins/*metabolism MH - Morpholines/pharmacology MH - Neuropeptides/*metabolism MH - Nuclear Proteins/*metabolism MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Phosphorylation MH - Protein Kinases/*metabolism MH - *Protein Serine-Threonine Kinases MH - Protein Structure, Tertiary MH - Proto-Oncogene Proteins/*metabolism MH - Proto-Oncogene Proteins c-akt MH - Ras Homolog Enriched in Brain Protein MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, LH/metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases MH - Time Factors MH - *Transcription Factors MH - Transfection MH - Up-Regulation MH - ras Proteins/*metabolism PMC - PMC1564189 MID - NIHMS11987 EDAT- 2004/02/26 05:00 MHDA- 2004/06/16 05:00 PMCR- 2008/01/28 CRDT- 2004/02/26 05:00 PHST- 2004/02/26 05:00 [pubmed] PHST- 2004/06/16 05:00 [medline] PHST- 2004/02/26 05:00 [entrez] PHST- 2008/01/28 00:00 [pmc-release] AID - S0021-9258(20)67047-8 [pii] AID - 10.1074/jbc.M401235200 [doi] PST - ppublish SO - J Biol Chem. 2004 May 7;279(19):19431-40. doi: 10.1074/jbc.M401235200. Epub 2004 Feb 24.