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Departments of Internal Medicine & Pharmacology (N.A.H.,
K.L.P.) Division of Reproductive Endocrinology (W.E.R.)
Department of Obstetrics & Gynecology University of Texas
Southwestern Medical Center Dallas, Texas 75390-8857
School of Biochemistry & Genetics (N.A.H., D.I.W.) Department
of Medicine (D.I.W., S.G.B.) University of Newcastle Newcastle
upon Tyne, United Kingdom
Cytochrome P450 17
-hydroxylase/17–20 lyase
(P450C17) is a critical branchpoint enzyme for
steroid hormone biosynthesis. During human gestation,
P450C17 is required for the production of
dehydroepiandrostenedione sulfate by the fetal adrenal cortex and
for testicular production of androgens that mediate male sexual
differentiation. In this study, we investigate the regulation of the
human CYP17 gene by two orphan nuclear receptors,
steroidogenic factor 1 (SF-1) and DAX1. In human embryos, SF-1 and DAX1
are expressed throughout the developing adrenal cortex from its
inception at 33 days post conception (dpc). In contrast,
P450C17 expression, which commences between 41
and 44 dpc, is limited to the fetal zone. The 5'-flanking region of the
human CYP17 gene contains three functional SF-1 elements
that collectively mediate a 
25-fold induction of promoter activity by
SF-1. In constructs containing all three functional SF-1 elements, DAX1
inhibited this activation by 55%. In the presence of only one or two
SF-1 elements, DAX1 inhibition was lost even though SF-1
transactivation persisted. These data suggest that efficient repression
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 the differential responses of various SF-1 target genes in
different endocrine tissues.
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