Glucocorticoids enhance activation of the human type II 3 beta -hydroxysteroid dehydrogenase/ Delta 5- Delta 4 isomerase gene

• Published in: The Journal of steroid biochemistry and molecular biology 2002-09, Vol.82 (1), p.55-63
• Main Authors: Feltus, F A, Cote, S, Simard, J, Gingras, S, Kovacs, W J, Nicholson, W E, Clark, B J, Melner, M H
• Format: Article
• Language: English
• ISSN: 0960-0760
• DOI: 10.1016/S0960-0760(02)00147-4

Glucocorticoids indirectly alter adrenocortical steroid output through the inhibition of ACTH secretion by the anterior pituitary. However, previous studies suggest that glucocorticoids can directly affect adrenocortical steroid production. Therefore, we have investigated the ability of glucocorticoids to affect transcription of adrenocortical steroid biosynthetic enzymes. One potential target of glucocorticoid action in the adrenal is an enzyme critical for adrenocortical steroid production: 3 beta -hydroxysteroid dehydrogenase/ Delta 5- Delta 4 isomerase (3 beta -HSD). Treatment of the adrenocortical cell line (H295R) with the glucocorticoid agonist dexamethasone (DEX) increased cortisol production and 3 beta -HSD mRNA levels alone or in conjunction with phorbol ester. This increase in 3 beta -HSD mRNA was paralleled by increases in Steroidogenic Acute Regulatory Protein (StAR) mRNA levels. The human type II 3 beta -HSD promoter lacks a consensus palindromic glucocorticoid response element (GRE) but does contain a Stat5 response element (Stat5RE) suggesting that glucocorticoids could affect type II 3 beta -HSD transcription via interaction with Stat5. Transfection experiments show enhancement of human type II 3 beta -HSD promoter activity by coexpression of the glucocorticoid receptor (GR) and Stat5A and treatment with 100 nM dexamethasone. Furthermore, removal of the Stat5RE either by truncation of the 5' flanking sequence in the promoter or introduction of point mutations to the Stat5RE abolished the ability of DEX to enhance 3 beta -HSD promoter activity. These studies demonstrate the ability of glucocorticoids to directly enhance the expression of an adrenal steroidogenic enzyme gene albeit independent of a consensus palindromic glucocorticoid response element.