GATA factors and the nuclear receptors, steroidogenic factor 1/liver receptor homolog 1, are key mutual partners in the regulation of the human 3beta-hydroxysteroid dehydrogenase type 2 promoter.
The human HSD3B2 gene encodes the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 2 (3beta-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.
Martin
Luc J
LJ
Ontogeny-Reproduction, Room T1-49, Centre Hospitalier de l'Université Laval Research Centre, 2705 Laurier Boulevard, Ste-Foy, Québec, Canada G1V 4G2.
Taniguchi
Hiroaki
H
Robert
Nicholas M
NM
Simard
Jacques
J
Tremblay
Jacques J
JJ
Viger
Robert S
RS
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics*; D009154:Mutation; D011375:Progesterone Reductase / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017384:Sequence Deletion; D013251:Steroid Isomerases / Q000235:genetics*; D054339:Steroidogenic Factor 1; D013256:Steroids / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D018398:Homeodomain Proteins; D009097:Multienzyme Complexes; C515057:NR5A1 protein, human; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D013256:Steroids; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D011375:Progesterone Reductase; D013251:Steroid Isomerases