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Submitted on November 17, 2005
Accepted on July 10, 2006
University of Michigan Medical School; Department of Molecular and Integrative Physiology; Program in Cellular and Molecular Biology; Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes; 109 Zina Pitcher Place, 1502 BSRB, Ann Arbor, MI 48109-2200
* To whom correspondence should be addressed. E-mail: ghammer{at}umich.edu.
Numerous genes required for adrenocortical steroidogenesis are activated by the nuclear hormone receptor 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 intra-adrenal negative feedback loop via activation of Dax-1 expression. Reporter constructs show glucocorticoid-dependent synergy between SF-1 and GR in the activation of Dax-1, which is antagonized by ACTH signaling. We map the functional GRE between -718bp and -704bp, required for activation by GR and synergy with SF-1. Of three SF-1 response elements, only the -128bp SF-1 response element is required for synergy with GR. ChIP assays demonstrate that dexamethasone treatment increases GR and SF-1 binding to the endogenous murine Dax-1 promoter 10-fold 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 while 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 Mc2r and 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.
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