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Nuclear Receptor Coregulators Differentially Modulate Induction and Glucocorticoid Receptor-Mediated Repression of the Corticotropin-Releasing Hormone Gene

Division of Medical Pharmacology, Leiden/Amsterdam Centre for Drug Research and Leiden University Medical Centre, 2300 RA Leiden, The Netherlands

Address all correspondence and requests for reprints to: S. van der Laan, Division of Medical Pharmacology, Leiden/Amsterdam Centre for Drug Research and Leiden University Medical Centre, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail: s.van.der.laan{at}lacdr.leidenuniv.nl.

Nuclear receptor coregulators are proteins that modulate the transcriptional activity of steroid receptors and may explain cell-specific effects of glucocorticoid receptor action. Based on the uneven distribution of a number of coregulators in CRH-expressing cells in the hypothalamus of the rat brain, we tested the hypothesis that these proteins are involved as mediators in the glucocorticoid-induced repression of the CRH promoter. Therefore, we assessed the role of coregulator proteins on both induction and repression of CRH in the AtT-20 cell line, a model system for CRH repression by glucocorticoids. The steroid receptor coactivator 1a (SRC1a), SRC-1e, nuclear corepressor (N-CoR), and silencing mediator of the retinoid and thyroid hormone receptor (SMRT) were studied in this system. We show that the concentration of glucocorticoid receptor and the type of ligand, i.e. corticosterone or dexamethasone, determines the repression. Furthermore, overexpression of SRC1a, but not SRC1e, increased both efficacy and potency of the glucocorticoid receptor-mediated repression of the forskolin-induced CRH promoter. Unexpectedly, cotransfection of the corepressors N-CoR and SMRT did not affect the corticosterone-dependent repression but resulted in a marked decrease of the forskolin stimulation of the CRH gene. Altogether, our data demonstrate that 1) the concentration of the receptor, 2) the type of ligand, and 3) the coregulator recruited all determine the expression and the repression of the CRH gene. We conclude that modulation of coregulator activity may play a role in the control of the hypothalamus-pituitary-adrenal axis.