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Role of the Phosphatidylinositol-3-Kinase and Extracellular Regulated Kinase Pathways in the Induction of Hypoxia-Inducible Factor (HIF)-1 Activity and the HIF-1 Target Vascular Endothelial Growth Factor in Ovarian Granulosa Cells in Response to Follicle-Stimulating Hormone

Departments of Cell and Molecular Biology (H.A., E.M., Y.P., M.H.-D.) and Medicine (E.J.L.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Division of Medicine (M.A.), University College, London WC1 E6JJ, United Kingdom; and the School of Molecular Biosciences (J.W.), Washington State University, Pullman, Washington 83843

Address all correspondence and requests for reprints to: Mary Hunzicker-Dunn, School of Molecular Biosciences, Washington State University, Pullman Washington 83843. E-mail: mehd{at}wsu.edu.

FSH stimulation of granulosa cells (GCs) results in increased hypoxia-inducible factor (HIF)-1 protein levels and HIF-1 activity that is necessary for up-regulation of certain FSH target genes including vascular endothelial growth factor. We report that the role of the phosphatidylinositol (PI)-3-kinase/AKT pathway in increasing HIF-1 protein in FSH-stimulated GCs extends beyond an increase in mammalian target of rapamycin-stimulated translation. FSH increases phosphorylation of the AKT target mouse double-minute 2 (MDM2); a phosphomimetic mutation of MDM2 is sufficient to induce HIF-1 activity. The PI3-kinase/AKT target forkhead box-containing protein O subfamily 1 (FOXO1) also effects the accumulation of HIF-1 as evidenced by the ability of a constitutively active FOXO1 mutant to inhibit the induction by FSH of HIF-1 protein and HIF-1 activity. Activation of the PI3-kinase/AKT pathway in GCs by IGF-I is sufficient to induce HIF-1 protein but surprisingly not HIF-1 activity. HIF-1 activity also appears to require a PD98059-sensitive protein (kinase) activity stimulated by FSH that is both distinct from mitogen-activated ERK kinase1/2 or 5 and independent of the PI3-kinase/AKT pathway. These results indicate that FSH-stimulated HIF-1 activation leading to up-regulation of targets such as vascular endothelial growth factor requires not only PI3-kinase/AKT-mediated activation of mammalian target of rapamycin as well as phosphorylation of FOXO1 and possibly MDM2 but also a protein (kinase) activity that is inhibited by the classic ERK kinase inhibitor PD98059 but not ERK1/2 or 5. Thus, regulation of HIF-1 activity in GCs by FSH under normoxic conditions is complex and requires input from multiple signaling pathways.

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