title: The role of hypoxia and HIF1α in the regulation of STAR-mediated steroidogenesis in granulosa cells.
abstract: The adaptive responses to hypoxia are mediated by hypoxia-inducible factor 1 alpha (HIF1α). Its role, however, in regulating steroidogenesis remains poorly understood. We examined the role of hypoxia and HIF1α in regulating steroid acute regulatory protein (STAR) expression and steroidogenesis in immortalized (KK1) mouse granulosa cells under progressively lowering O2 concentrations (20%, 15%, 10%, 5%, 1%). Basal and dbcAMP-stimulated progesterone synthesis was decreased under severe hypoxia (1% and 5% O2). The partial hypoxia revealed opposing effects, with a significant increase in steroidogenic response at 10% O2 in dbcAMP-treated cells: Star-promoter activity, mRNA and protein expression were increased. The hypoxia-stimulated STAR expression was PKA-dependent. Binding of HIF1α to the Star-promoter was potentiated under partial hypoxia. Inhibition of the transcriptional activity or expression of HIF1α suppressed STAR-expression. HIF1α appears to be a positive regulator of basal and stimulated STAR-expression, which under partial hypoxia is capable of increasing the steroidogenic capacity of granulosa cells.
authors.affiliation: Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. Electronic address: kowalewskipl@yahoo.de.
authors.forename: Mariusz Pawel
authors.initials: MP
authors.lastname: Kowalewski
authors.affiliation: Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
authors.forename: Aykut
authors.initials: A
authors.lastname: Gram
authors.affiliation: Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
authors.forename: Alois
authors.initials: A
authors.lastname: Boos
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000494:pharmacology*; D015687:Cell Hypoxia; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D011374:Progesterone; D003994:Bucladesine; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: HIF1α; KK1 granulosa cells; STAR; Steroidogenesis