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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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E. Lalli and P. Sassone-Corsi DAX-1, an Unusual Orphan Receptor at the Crossroads of Steroidogenic Function and Sexual Differentiation Mol. Endocrinol., August 1, 2003; 17(8): 1445 - 1453. [Abstract] [Full Text] [PDF]
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B. M. Gummow, J. N. Winnay, and G. D. Hammer Convergence of Wnt Signaling and Steroidogenic Factor-1 (SF-1) on Transcription of the Rat Inhibin {alpha} Gene J. Biol. Chem., July 11, 2003; 278(29): 26572 - 26579. [Abstract] [Full Text] [PDF]
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Z. Chai, P. Brereton, T. Suzuki, H. Sasano, V. Obeyesekere, G. Escher, R. Saffery, P. Fuller, C. Enriquez, and Z. Krozowski 17{beta}-Hydroxysteroid Dehydrogenase Type XI Localizes to Human Steroidogenic Cells Endocrinology, May 1, 2003; 144(5): 2084 - 2091. [Abstract] [Full Text] [PDF]
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H. Osman, C. Murigande, A. Nadakal, and A. M. Capponi Repression of DAX-1 and Induction of SF-1 Expression. TWO MECHANISMS CONTRIBUTING TO THE ACTIVATION OF ALDOSTERONE BIOSYNTHESIS IN ADRENAL GLOMERULOSA CELLS J. Biol. Chem., October 18, 2002; 277(43): 41259 - 41267. [Abstract] [Full Text] [PDF]
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F. Gizard, B. Lavallee, F. DeWitte, E. Teissier, B. Staels, and D. W. Hum The Transcriptional Regulating Protein of 132 kDa (TReP-132) Enhances P450scc Gene Transcription through Interaction with Steroidogenic Factor-1 in Human Adrenal Cells J. Biol. Chem., October 11, 2002; 277(42): 39144 - 39155. [Abstract] [Full Text] [PDF]
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B. Gurates, S. Sebastian, S. Yang, J. Zhou, M. Tamura, Z. Fang, T. Suzuki, H. Sasano, and S. E. Bulun WT1 and DAX-1 Inhibit Aromatase P450 Expression in Human Endometrial and Endometriotic Stromal Cells J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4369 - 4377. [Abstract] [Full Text] [PDF]
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 S. G. Lehmann, E. Lalli, and P. Sassone-Corsi From the Cover: X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein PNAS, June 11, 2002; 99(12): 8225 - 8230. [Abstract] [Full Text] [PDF]
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P. S. Babu, D. L. Bavers, F. Beuschlein, S. Shah, B. Jeffs, J. L. Jameson, and G. D. Hammer Interaction Between Dax-1 and Steroidogenic Factor-1 in Vivo: Increased Adrenal Responsiveness to ACTH in the Absence of Dax-1 Endocrinology, February 1, 2002; 143(2): 665 - 673. [Abstract] [Full Text] [PDF]
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D. Lopez, W. Shea-Eaton, M. D. Sanchez, and M. P. McLean DAX-1 Represses the High-Density Lipoprotein Receptor Through Interaction with Positive Regulators Sterol Regulatory Element-Binding Protein-1a and Steroidogenic Factor-1 Endocrinology, December 1, 2001; 142(12): 5097 - 5106. [Abstract] [Full Text] [PDF]
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C. J. Lin, J. W. M. Martens, and W. L. Miller NF-1C, Sp1, and Sp3 Are Essential for Transcription of the Human Gene for P450c17 (Steroid 17{alpha}-hydroxylase/17,20 lyase) in Human Adrenal NCI-H295A Cells Mol. Endocrinol., August 1, 2001; 15(8): 1277 - 1293. [Abstract] [Full Text] [PDF]
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T. Sugawara, S. Abe, N. Sakuragi, Y. Fujimoto, E. Nomura, K. Fujieda, M. Saito, and S. Fujimoto RIP 140 Modulates Transcription of the Steroidogenic Acute Regulatory Protein Gene through Interactions with Both SF-1 and DAX-1 Endocrinology, August 1, 2001; 142(8): 3570 - 3577. [Abstract] [Full Text] [PDF]
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