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GATA Factors and the Nuclear Receptors, Steroidogenic Factor 1/Liver Receptor Homolog 1, Are Key Mutual Partners in the Regulation of the Human 3ß-Hydroxysteroid Dehydrogenase Type 2 Promoter

Ontogeny-Reproduction Research Unit (L.J.M., H.T., N.M.R., J.J.T., R.S.V.) and Cancer Genomics Laboratory (J.S.), Molecular Endocrinology and Oncology Research Unit (J.S.), Centre Hospitalier de l’Université Laval Research Centre, Ste-Foy, Québec, Canada G1V 4G2; Centre de Recherche en Biologie de la Reproduction (J.J.T., R.S.V.) and Department of Obstetrics and Gynecology (J.J.T., R.S.V.) and Department of Anatomy and Physiology (J.S.), Faculty of Medicine, Université Laval, Ste-Foy, Québec, Canada G1K 7P4

Address all correspondence and requests for reprints to: Dr. Jacques J. Tremblay or Dr. Robert S. Viger, Ontogeny-Reproduction, Room T1-49, CHUL Research Centre, 2705 Laurier Boulevard, Ste-Foy, Québec, Canada G1V 4G2. E-mail addresses: Jacques-J.Tremblay{at}crchul.ulaval.ca; and Robert.Viger{at}crchul.ulaval.ca.

The human HSD3B2 gene encodes the 3ß-hydroxysteroid dehydrogenase/⁵-⁴ isomerase type 2 (3ß-HSD2) enzyme that is required for steroid hormone biosynthesis. Mutations in the hHSD3B2 gene are responsible for a form of congenital adrenal hyperplasia and male pseudohermaphroditism whereas overexpression of hHSD3B2 has been recently associated with polycystic ovarian syndrome. 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 –1073 bp 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 –196 bp 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, steroidogenic factor 1 and liver receptor homolog 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.

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