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; Mary Hunzicker-Dunn

doi:10.1074/jbc.M401235200

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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

Journal article

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Peer reviewed

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

The Journal of biological chemistry, Vol.279(19), pp.19431-19440

05/07/2004

DOI: https://doi.org/10.1074/jbc.M401235200

Handle:

https://hdl.handle.net/2376/104242

PMCID: PMC1564189

PMID: 14982927

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Abstract

Protein Kinases - metabolism

Up-Regulation

Phosphorylation

Luciferases - metabolism

Microtubule-Associated Proteins - metabolism

Protein-Serine-Threonine Kinases

Receptors, LH - metabolism

ras Proteins - metabolism

Ras Homolog Enriched in Brain Protein

Phosphatidylinositol 3-Kinases - metabolism

Hypoxia-Inducible Factor 1, alpha Subunit

DNA-Binding Proteins - metabolism

Transfection

Genes, Dominant

Time Factors

Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit

Female

Cell Differentiation

Chromones - pharmacology

Genes, Reporter

Cyclic AMP-Dependent Protein Kinases - metabolism

Protein Structure, Tertiary

Proto-Oncogene Proteins - metabolism

Follicle Stimulating Hormone - metabolism

Hypoxia-Inducible Factor 1

Ribosomal Protein S6 Kinases, 70-kDa - metabolism

Signal Transduction

Enzyme Inhibitors - pharmacology

Morpholines - pharmacology

Rats

Neuropeptides - metabolism

Nuclear Proteins - metabolism

Rats, Sprague-Dawley

Proto-Oncogene Proteins c-akt

Animals

Inhibins - metabolism

Monomeric GTP-Binding Proteins - metabolism

Models, Biological

TOR Serine-Threonine Kinases

Transcription Factors

Enzyme Activation

Granulosa Cells - cytology

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.

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Title: 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
Creators: Hena Alam - Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
Evelyn T Maizels
Youngkyu Park
Shail Ghaey
Zachary J Feiger
Navdeep S Chandel
Mary Hunzicker-Dunn
Publication Details: The Journal of biological chemistry, Vol.279(19), pp.19431-19440
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: P01 HD 21921 / NICHD NIH HHS GM 60472-05 / NIGMS NIH HHS R01 GM060472 / NIGMS NIH HHS P01 HL071643 / NHLBI NIH HHS P01 HD021921 / NICHD NIH HHS P01 HL 071643 / NHLBI NIH HHS T32 HD 07086 / NICHD NIH HHS
Identifiers: 99900546736701842
Language: English
Resource Type: Journal article