Glucocorticoids enhance activation of the human type II 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase gene.
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: 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD). Treatment of the adrenocortical cell line (H295R) with the glucocorticoid agonist dexamethasone (DEX) increased cortisol production and 3beta-HSD mRNA levels alone or in conjunction with phorbol ester. This increase in 3beta-HSD mRNA was paralleled by increases in Steroidogenic Acute Regulatory Protein (StAR) mRNA levels. The human type II 3beta-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 3beta-HSD transcription via interaction with Stat5. Transfection experiments show enhancement of human type II 3beta-HSD promoter activity by coexpression of the glucocorticoid receptor (GR) and Stat5A and treatment with 100nM 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 3beta-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.
Feltus
F Alex
FA
Department of OB/GYN, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. yaqona2@yahoo.com
Cote
Stephanie
S
Simard
Jacques
J
Gingras
Sebastien
S
Kovacs
William J
WJ
Nicholson
Wendell E
WE
Clark
Barbara J
BJ
Melner
Michael H
MH
D000306:Adrenal Cortex Neoplasms / Q000201:enzymology*; D000616:Aminoglutethimide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006367:HeLa Cells / Q000201:enzymology; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D008894:Milk Proteins; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011375:Progesterone Reductase / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D050799:STAT5 Transcription Factor; D013251:Steroid Isomerases / Q000096:biosynthesis / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D025521:Tumor Suppressor Proteins; D000098682:Steroidogenic Acute Regulatory Protein
C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D008894:Milk Proteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000098682:Steroidogenic Acute Regulatory Protein; D000616:Aminoglutethimide; D003907:Dexamethasone; D011375:Progesterone Reductase; D013251:Steroid Isomerases; D013755:Tetradecanoylphorbol Acetate; D006854:Hydrocortisone