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Submitted on July 7, 2004
Accepted on October 15, 2004
Ontogeny-Reproduction Research Unit, CHUL Research Centre, Ste-Foy, Québec, Canada; Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Ste-Foy, Québec, Canada
* To whom correspondence should be addressed. E-mail: Jacques-J.Tremblay{at}crchul.ulaval.ca.
The human 3
-hydroxysteroid dehydrogenase/
5-4 isomerase type 2 (3-HSD2) enzyme, encoded by the hHSD3B2 gene, is mainly found in the gonads and adrenals. This enzyme catalyzes an essential early step in the biosynthesis of all classes of steroid hormones. The critical nature of enzyme is supported by the occurrence of human syndromes that are associated with insufficient 3-HSD2 expression and/or activity. Although the need for a functional 3-HSD2 enzyme is indisputable, the molecular mechanisms that regulate HSD3B2 expression (both basal and hormone-induced) in steroidogenic cells remain poorly understood. A role for the Nur77 family of immediate early orphan nuclear receptors in steroidogenesis has received recent interest. For example, Nur77 is present in the gonads and adrenals where its expression is robustly and rapidly induced by hormones that stimulate steroidogenic gene expression. Moreover, the expression patterns of Nur77 and at least one key steroidogenic gene (hHSD3B2) closely parallel one another. We now report that the hHSD3B2 promoter is indeed a novel target for Nur77 both in testicular Leydig cells and in adrenal cells. We have mapped a novel response element located at -130bp specific for Nur77 and not other orphan nuclear receptors (SF-1 and LRH-1) previously shown to regulate hHSD3B2 promoter activity. This Nur77 element is essential and sufficient to confer Nur77-responsiveness to the hHSD3B2 promoter and its mutation blunts the basal and hormone-induced hHSD3B2 promoter activity in steroidogenic cells. We also show that Nur77 synergizes with all members of the SRC family of co-activators on the hHSD3B2 promoter. Taken together, our identification of Nur77 as an important regulator of HSD3B2 promoter activity helps us to better define the tissue-specific and hormonal regulation of the HSD3B2 gene in steroidogenic cells.
-HSD •
Nur77 •
NGFI-B •
NR4A1 •
NBRE •
Immediate early •
Synergy •
Co-activator
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