title: Activins regulate 17beta-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells.
abstract: Activins are pleiotropic members of the TGFbeta superfamily and were initially characterized based on their abilities to stimulate FSH synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD1; Hsd17b1), as an activin-responsive gene in immortalized gonadotrope cells, LbetaT2. 17beta-HSD1 catalyzes the conversion of estrone to the more active 17beta-estradiol, and activin A stimulated an increase in this enzymatic activity in these cells. We demonstrated that activins signaled via the type I receptor, activin receptor-like kinase (ALK4), and the intracellular signaling protein, SMAD2, to regulate Hsd17b1 transcription in immediate-early fashion. Critical cis-elements, including a minimal SMAD-binding element, were mapped to within 100 bp of the start of transcription. Activin/ALK4 signaling also regulated Hsd17b1 transcription in both immortalized and primary cultured murine granulosa cells. The promoter regions mediating basal and activin/ALK4-regulated promoter activity were generally conserved across the different cell types. The data show that activin A rapidly regulates Hsd17b1 transcription in gonadotrope and granulosa cells and may thereby regulate local 17beta-estradiol synthesis.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Beata
authors.initials: B
authors.lastname: Bak
authors.forename: Laura
authors.initials: L
authors.lastname: Carpio
authors.forename: Jinjing L
authors.initials: JL
authors.lastname: Kipp
authors.forename: Pankaj
authors.initials: P
authors.lastname: Lamba
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Ren-Shan
authors.initials: RS
authors.lastname: Ge
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hardy
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Mayo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D028341:Activins / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004958:Estradiol / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D052681:Gonadotrophs / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D051899:Smad2 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D034741:RNA, Small Interfering; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C422405:activin A; D028341:Activins; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D030201:Activin Receptors, Type I; C498933:Acvr1b protein, mouse