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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0460v1 201/1/89    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bak, B. Articles by Bernard, D. Search for Related Content PubMed PubMed Citation Articles by Bak, B. Articles by Bernard, D.

B Bak, Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
L Carpio, Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
J Kipp, Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, United States
P Lamba, Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Y Wang, Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
R Ge, Center for Biomedical Research, Population Council, New York, United States
M Hardy, Center for Biomedical Research, Population Council, New York, United States
K Mayo, Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, United States
D Bernard, Pharmacology and Therapeutics, McGill University , Montreal, Quebec, H3G 1Y6, Canada

Correspondence: Daniel Bernard, Email: daniel.bernard{at}mcgill.ca

Abstract

Activins are pleiotropic members of the TGFβ superfamily and were initially characterized based on their abilities to stimulate follicle-stimulating hormone (FSH) synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17β-hydroxysteroid dehydrogenase type I (17β-HSD1; Hsd17b1), as an activin-responsive gene in immortalized gonadotrope cells, LβT2. 17β-HSD1 catalyzes the conversion of estrone to the more active 17β-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 17β-estradiol synthesis.