This Article Full Text Full Text (PDF) All Versions of this Article: 20/11/2711    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gummow, B. M. Articles by Hammer, G. D. Search for Related Content PubMed PubMed Citation Articles by Gummow, B. M. Articles by Hammer, G. D.

Reciprocal Regulation of a Glucocorticoid Receptor-Steroidogenic Factor-1 Transcription Complex on the Dax-1 Promoter by Glucocorticoids and Adrenocorticotropic Hormone in the Adrenal Cortex

University of Michigan Medical School, Department of Molecular and Integrative Physiology (B.M.G., G.D.H.), Program in Cellular and Molecular Biology (J.O.S.), Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes (G.D.H.), Ann Arbor, Michigan 48109-2200

Address all correspondence and requests for reprints to: Gary D. Hammer, M.D., Ph.D., 109 Zina Pitcher Place, 1502 BSRB, Ann Arbor, Michigan 48109-2200. E-mail: ghammer{at}umich.edu.

Numerous genes required for adrenocortical steroidogenesis are activated by the nuclear hormone receptor steroidogenic factor 1 (SF-1) (NR5A1). Dax-1 (NR0B1), another nuclear hormone receptor, represses SF-1-dependent activation. Glucocorticoid products of the adrenal cortex provide negative feedback to the production of hypothalamic CRH and pituitary ACTH. We hypothesized that glucocorticoids stimulate an intraadrenal negative feedback loop via activation of Dax-1 expression. Reporter constructs show glucocorticoid-dependent synergy between SF-1 and glucocorticoid receptor (GR) in the activation of Dax-1, which is antagonized by ACTH signaling. We map the functional glucocorticoid response element between –718 and –704 bp, required for activation by GR and synergy with SF-1. Of three SF-1 response elements, only the –128-bp SF-1 response element is required for synergy with GR. Chromatin immunoprecipitation (ChIP) assays demonstrate that dexamethasone treatment increases GR and SF-1 binding to the endogenous murine Dax-1 promoter 10- and 3.5-fold over baseline. Serial ChIP assays reveal that that GR and SF-1 are part of the same complex on the Dax-1 promoter, whereas coimmunoprecipitation assay confirms the presence of a protein complex that contains both GR and SF-1. ACTH stimulation disrupts the formation of this complex by abrogating SF-1 binding to the Dax-1 promoter, while promoting SF-1 binding to the melanocortin-2 receptor (Mc2r) and steroidogenic acute regulatory protein (StAR) promoters. Finally, dexamethasone treatment increases endogenous Dax-1 expression and concordantly decreases StAR expression. ACTH signaling antagonizes the increase in Dax-1 yet strongly activates StAR transcription. These data indicate that GR provides feedback regulation of adrenocortical steroid production through synergistic activation of Dax-1 with SF-1, which is antagonized by ACTH activation of the adrenal cortex.

This article has been cited by other articles:

				L. J Martin and J. J Tremblay Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1 J. Mol. Endocrinol., September 1, 2008; 41(3): 165 - 175. [Abstract] [Full Text] [PDF]

				J. Zhou, R. H. Oakley, and J. A. Cidlowski DAX-1 (Dosage-Sensitive Sex Reversal-Adrenal Hypoplasia Congenita Critical Region on the X-Chromosome, Gene 1) Selectively Inhibits Transactivation But Not Transrepression Mediated by the Glucocorticoid Receptor in a LXXLL-Dependent Manner Mol. Endocrinol., July 1, 2008; 22(7): 1521 - 1534. [Abstract] [Full Text] [PDF]

				X. Huang, B. Jiao, C. K. Fung, Y. Zhang, W. K K Ho, C. B. Chan, H. Lin, D. Wang, and C. H K Cheng The presence of two distinct prolactin receptors in seabream with different tissue distribution patterns, signal transduction pathways and regulation of gene expression by steroid hormones J. Endocrinol., August 1, 2007; 194(2): 373 - 392. [Abstract] [Full Text] [PDF]

				A. A. Verrijn Stuart, G. Ozisik, M. A. de Vroede, J. C. Giltay, R. J. Sinke, T. J. Peterson, R. M. Harris, J. Weiss, and J. L. Jameson An Amino-Terminal DAX1 (NROB1) Missense Mutation Associated with Isolated Mineralocorticoid Deficiency J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 755 - 761. [Abstract] [Full Text] [PDF]