DAX-1 blocks steroid production at multiple levels.
DAX-1 is an unusual member of the nuclear hormone receptor superfamily whose expression is mainly, but not uniquely, restricted to steroidogenic tissues. We have recently shown that DAX-1 can block the first and rate-limiting step in steroid biosynthesis by repressing StAR (steroidogenic acute regulatory protein) expression. Here we show that DAX-1 blocks steroid production at multiple levels in the Y-1 mouse adrenocortical tumor cell line. Expression of DAX-1 in Y-1 cells significantly impairs both basal and cAMP-stimulated steroid production, without affecting the functionality of the cAMP-responsive PKA pathway. Experiments using an hydroxylated cholesterol derivative show that biochemical steps in steroidogenesis subsequent to cholesterol delivery to mitochondria are also impaired in Y-1 cells expressing DAX-1. This is explained by the repression of P450scc and 3beta-HSD expression, in addition to StAR. DAX-1 expression in Y-1 cells results in the inhibition of the activity of the StAR, P450scc and 3beta-HSD promoters. An inappropriate steroidogenic block in the male fetus might have an important role in the pathogenesis of sex reversal syndromes caused by a duplication of the genomic region of the X chromosome containing the DAX-1 gene.
Lalli
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Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, Strasbourg, France.
Melner
M H
MH
Stocco
D M
DM
Sassone-Corsi
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P
D015096:3-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000096:biosynthesis / Q000235:genetics; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000502:physiology; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000502:physiology; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D013256:Steroids / Q000096:biosynthesis*; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured; D000098682:Steroidogenic Acute Regulatory Protein
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; C539966:Nr0b1 protein, mouse; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D013256:Steroids; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; D000242:Cyclic AMP; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme; D017868:Cyclic AMP-Dependent Protein Kinases