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 steroidog enic tissues. We have recently shown that DAX-1 can block the first an d rate-limiting step in steroid biosynthesis by repressing StAR (stero idogenic acute regulatory protein) expression. Here we show that DAX-1 blocks steroid production at multiple levels in the Y-1 mouse adrenoc ortical tumor cell line. Expression of DAX-1 in Y-l cells significantl y impairs both basal and cAMP-stimulated steroid production, without a ffecting the functionality of the cAMP-responsive PKA pathway. Experim ents using an hydroxylated cholesterol derivative show that biochemica l steps in steroidogenesis subsequent to cholesterol delivery to mitoc hondria are also impaired in Y-1 cells expressing DAX-1. This is expla ined by the repression of P450scc and 3 beta-HSD expression, in additi on to StAR. DAX-1 expression in Y-1 cells results in the inhibition of the activity of the StAR, P450scc and 3 beta-HSD promoters. An inappr opriate steroidogenic block. in the male fetus might have an important role in the pathogenesis of sex reversal syndromes caused by a duplic ation of the genomic region of the X chromosome containing the DAX-1 g ene.