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The Glucocorticoid Receptor and the Orphan Nuclear Receptor Chicken Ovalbumin Upstream Promoter-Transcription Factor II Interact with and Mutually Affect Each Other’s Transcriptional Activities: Implications for Intermediary Metabolism

Pediatric and Reproductive Endocrinology Branch (M.U.D., S.A., T.I., G.P.C., T.K.), National Institute of Child Health and Human Development, and Growth and Development Section (N.B.), Diabetes Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Tomoshige Kino, M.D., Ph.D., Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Mail Stop Code 1583, Building 10, Room 9D42, Bethesda, Maryland 20892-1583. E-mail: kinot{at}mail.nih.gov.

Glucocorticoids exert their metabolic effect via their intracellular receptor, the glucocorticoid receptor (GR). In a yeast two-hybrid screening, we found the chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), an orphan nuclear receptor that plays important roles in glucose, cholesterol, and xenobiotic metabolism, as a partner of GR. In an in vitro glutathione-S-transferase pull-down assay, COUP-TFII interacted via its DNA-binding domain with the hinge regions of both GR and its splicing variant GRß, whereas COUP-TFII formed a complex with GR, but not with GRß, in an in vivo chromatin immunoprecipitation and a regular immunoprecipitation assay. Accordingly, GR, but not GRß, enhanced COUP-TFII-induced transactivation of the simple COUP-TFII-responsive 7-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas COUP-TFII repressed GR-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors. Importantly, mutual protein-protein interaction of GR and COUP-TFII was necessary for glucocorticoid-induced enhancement of the promoter activity and the endogenous mRNA expression of the COUP-TFII-responsive phosphoenolpyruvate carboxykinase, the rate-limiting enzyme of hepatic gluconeogenesis. We suggest that COUP-TFII may participate in some of the metabolic effects of glucocorticoids through direct interactions with GR. These interactions influence the transcription of both COUP-TFII- and GR-responsive target genes, seem to be promoter specific, and can be in either a positive or negative direction.

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