ArticleEndocrinology2009
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.
Article in Endocrinology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 118 citations in OpenAlex.
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- Expression of Follicle-Stimulating Hormone Receptor in Von Hippel-Lindau Associated Tumors and Cysts: An Immunohistochemical Study.Journal of kidney cancer and VHL · 2025Article
- EPAS1 expression contributes to maintenance of the primordial follicle pool in the mouse ovary.Scientific reports · 2024Article
- Targeting the FSH/FSHR axis in ovarian cancer: advanced treatment using nanotechnology and immunotherapy.Frontiers in endocrinology · 2024Review
- Effects of follicle-stimulating hormone on the proliferation and apoptosis of infantile hemangioma stem cells.Biochemistry and biophysics reports · 2023Article
- Extra-Gonadal and Non-Canonical Effects of FSH in Males.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Impact of Follicle Stimulating Hormone Receptor (FSHR) Polymorphism on the Efficiency of Co-Treatment with Growth Hormone in a Group of Infertile Women from Romania.Diagnostics (Basel, Switzerland) · 2022Article
- Expression and distribution patterns of VEGF, TGF-βVeterinary medicine and science · 2022Article
- Overview of follicle stimulating hormone and its receptors in reproduction and in stem cells and cancer stem cells.International journal of biological sciences · 2022Review
- Association of anJournal of personalized medicine · 2020Article
- WIPI2 depletion inhibits the growth of hepatocellular carcinoma cells through the AMPK signaling pathway.Oncology reports · 2020Article
- Cross-Species Insights Into Genomic Adaptations to Hypoxia.Frontiers in genetics · 2020Review
- Progress in the treatment of infantile hemangioma.Annals of translational medicine · 2019Review
- C/EBPβ regulates Vegf gene expression in granulosa cells undergoing luteinization during ovulation in female rats.Scientific reports · 2019Article
- Considering the Role of Murine Double Minute 2 in the Cardiovascular System?Frontiers in cell and developmental biology · 2019Review
- Role of mTOR Signaling in Female Reproduction.Frontiers in endocrinology · 2019Review
- Gonadotropin regulation of ankyrin-repeat and SOCS-box protein 9 (ASB9) in ovarian follicles and identification of binding partners.PloS one · 2019Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.