| pubmed-article:18845636 | rdf:type | pubmed:Citation | lld:pubmed |
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| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0018207 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0078058 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0521119 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0733758 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0031727 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0215848 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0441655 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C1704632 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0871261 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C2348977 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C1822686 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C2348110 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C1171892 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C2911692 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C1706817 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C1704259 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C1521761 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C1705987 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0851285 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C0205263 | lld:lifeskim |
| pubmed-article:18845636 | lifeskim:mentions | umls-concept:C1521840 | lld:lifeskim |
| pubmed-article:18845636 | pubmed:issue | 2 | lld:pubmed |
| pubmed-article:18845636 | pubmed:dateCreated | 2009-1-29 | lld:pubmed |
| pubmed-article:18845636 | pubmed:abstractText | 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. | lld:pubmed |
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