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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

 Hena Alam  ;  Jennifer Weck  ;  Evelyn Maizels  ;  Youngkyu Park  ;  Eun Jig Lee  ;  Margaret Ashcroft  ;  Mary Hunzicker-Dunn 
 ENDOCRINOLOGY, Vol.150(2) : 915-928, 2009 
Journal Title
Issue Date
Animals ; Cells, Cultured ; Extracellular Signal-Regulated MAP Kinases/physiology* ; Female ; Follicle Stimulating Hormone/pharmacology* ; Forkhead Transcription Factors/antagonists & inhibitors ; Granulosa Cells/drug effects* ; Granulosa Cells/metabolism ; Hypoxia-Inducible Factor 1/metabolism* ; Insulin-Like Growth Factor I/pharmacology ; Nerve Tissue Proteins/antagonists & inhibitors ; Ovary/drug effects* ; Ovary/metabolism ; Phosphatidylinositol 3-Kinases/physiology* ; Phosphorylation/drug effects ; Protein Kinases/physiology ; Proto-Oncogene Proteins c-mdm2/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Signal Transduction/physiology ; TOR Serine-Threonine Kinases ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor A/metabolism*
FSH stimulation of granulosa cells (GCs) results in increased hypoxia-inducible factor (HIF)-1alpha 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-1alpha 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-1alpha as evidenced by the ability of a constitutively active FOXO1 mutant to inhibit the induction by FSH of HIF-1alpha protein and HIF-1 activity. Activation of the PI3-kinase/AKT pathway in GCs by IGF-I is sufficient to induce HIF-1alpha 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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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
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