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Submitted on June 25, 2004
Accepted on May 24, 2005
Ontogeny-Reproduction Research Unit, CHUL Research Centre, Ste-Foy, Québec, Canada; Centre de Recherche en Biologie de la Reproduction (CRBR), Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Ste-Foy, Québec, Canada; Cancer Genomics Laboratory, Molecular Endocrinology and Oncology Research Unit, CHUL Research Centre, Ste-Foy, Québec, Canada; Department of Anatomy and Physiology, Faculty of Medicine, Université Laval, Ste-Foy, Québec, Canada
* To whom correspondence should be addressed. E-mail: Jacques-J.Tremblay{at}crchul.ulaval.ca or Robert.Viger{at}crchul.ulaval.ca.
The human HSD3B2 gene encodes the 3
-hydroxysteroid dehydrogenase/
5-4 isomerase type 2 (3-HSD2) enzyme that is required for steroid hormone biosynthesis. Mutations in the hHSD3B2 gene are responsible for a form of congenital adrenal hyperplasia (CAH) and male pseudohermaphroditism while overexpression of hHSD3B2 has been recently associated with polycystic ovarian syndrome (PCOS). Despite the importance of the hHSD3B2 gene, the molecular mechanisms that regulate its expression remain poorly understood. Transcription factors belonging to the GATA family are emerging as novel regulators of steroidogenesis. Indeed, GATA-4 and GATA-6 are abundantly expressed in steroidogenic cells of the gonads and adrenals. We now report that the human HSD3B2 promoter (hHSD3B2), which contains four consensus GATA elements, constitutes an important target for GATA factors. GATA-4 and GATA-6 by themselves are sufficient to activate transcription (up to 15 fold) from a -1073bp hHSD3B2 promoter fragment and blockade of endogenous GATA expression and/or activity blunts hHSD3B2 promoter activity in steroidogenic cells. Deletion studies showed that the proximal GATA element located at -196bp is sufficient to confer GATA responsiveness of the hHSD3B2 promoter and is required for full hHSD3B2 promoter activity in steroidogenic cells. Moreover, we report that GATA-4 and GATA-6 can physically interact with the nuclear receptors SF-1 and LRH-1 to synergistically activate hHSD3B2 promoter activity in both homologous and heterologous cells. Aberrant expression of transcription factors essential for hHSD3B2 expression might also be involved in some pathologies/syndromes associated with deregulated hHSD3B2 expression.
-hydroxysteroid dehydrogenase/5-4 isomerase type 2 •
Steroidogenesis •
Transcription •
Synergism
NURSA Molecule Pages Link:
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