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PMID: 14982927 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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.

The Journal of biological chemistry ·Vol. 279 ·No. 19 ·2004-05-07 ·Pages 19431-40

Alam H, Maizels ET, Park Y, Ghaey S, Feiger ZJ, Chandel NS, Hunzicker-Dunn M

Abstract

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.

MeSH Terms
Animals Cell Differentiation Chromones/pharmacology Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit Cyclic AMP-Dependent Protein Kinases/metabolism DNA-Binding Proteins/metabolism Enzyme Activation Enzyme Inhibitors/pharmacology Female Follicle Stimulating Hormone/metabolism Genes, Dominant Genes, Reporter Granulosa Cells/cytology Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Inhibins/metabolism Luciferases/metabolism Microtubule-Associated Proteins/metabolism Models, Biological Monomeric GTP-Binding Proteins/metabolism Morpholines/pharmacology Neuropeptides/metabolism Nuclear Proteins/metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Protein Kinases/metabolism Protein Serine-Threonine Kinases Protein Structure, Tertiary Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-akt Ras Homolog Enriched in Brain Protein Rats Rats, Sprague-Dawley Receptors, LH/metabolism Ribosomal Protein S6 Kinases, 70-kDa/metabolism Signal Transduction TOR Serine-Threonine Kinases Time Factors Transcription Factors Transfection Up-Regulation ras Proteins/metabolism
Chemicals
Chromones Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit DNA-Binding Proteins Enzyme Inhibitors Hif1a protein, rat Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Microtubule-Associated Proteins Morpholines Neuropeptides Nuclear Proteins Prkar2b protein, rat Proto-Oncogene Proteins Ras Homolog Enriched in Brain Protein Receptors, LH Rheb protein, rat Transcription Factors inhibin-alpha subunit 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one Inhibins Follicle Stimulating Hormone Luciferases Protein Kinases mTOR protein, rat Akt1 protein, rat Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases, 70-kDa TOR Serine-Threonine Kinases Cyclic AMP-Dependent Protein Kinases Monomeric GTP-Binding Proteins ras Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Alam Hena
Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Maizels Evelyn T
Park Youngkyu
Ghaey Shail
Feiger Zachary J
Chandel Navdeep S
Hunzicker-Dunn Mary
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M401235200
Published
2004-05-07
Epub
2004-00-24
Pages
19431-40
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC1564189
Subset
IM
Grants
NICHD NIH HHS · P01 HD021921 · United States
NICHD NIH HHS · T32 HD 07086 · United States
NIGMS NIH HHS · GM 60472-05 · United States
NHLBI NIH HHS · P01 HL071643 · United States
NHLBI NIH HHS · P01 HL 071643 · United States
NICHD NIH HHS · P01 HD 21921 · United States
NIGMS NIH HHS · R01 GM060472 · United States
External Links
PubMed source DOI: 10.1074/jbc.M401235200 PMC Full Text View journal details
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