Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: Potential interactions in gene regulation

Cytochrome P450 17 alpha -hydroxylase/17-20 lyase (P450(C17)) is a critical branchpoint enzyme for steroid hormone biosynthesis. During human gestatio n, P450(C17) is required for the production of dehydroepiandrostenedione su lfate by the fetal adrenal cortex and for testicular production of androgen s that mediate male sexual differentiation. In this study, we investigate t he regulation of the human CYP17 gene by two orphan nuclear receptors, ster oidogenic factor 1 (SF-1) and DAX1. In human embryos, SF-1 and DAX1 are exp ressed throughout the developing adrenal cortex from its inception at 33 da ys post conception (dpc). In contrast, P450(C17) expression, which commence s between 41 and 44 dpc, is limited to the fetal zone. The 5'-flanking regi on of the human CYP17 gene contains three functional SF-1 elements that col lectively mediate a greater than or equal to 25-fold induction of promoter activity by SF-1. In constructs containing all three functional SF-1 elemen ts, DAX1 inhibited this activation by greater than or equal to 55%. In the presence of only one or two SF-1 elements, DAX1 inhibition was lost even th ough SF-1 transactivation persisted. These data suggest that efficient repr ession of SF-1-mediated activation of the human CYP17 gene by DAX1 requires multiple SF-1 elements. Opposing effects of SF-1 and DAX1 may fine tune th e differential responses of various SF-1 target genes in different endocrin e tissues.