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Submitted on September 5, 2003
Accepted on January 14, 2004
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA., Growth and Development Section, Diabetes Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
* To whom correspondence should be addressed. E-mail: kinot{at}mail.nih.gov.
Glucocorticoids exert their metabolic effect via its 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 GST pull-down assay, COUP-TFII interacted via its DNA-binding domain with the "hinge" regions of both GR
and its splicing variant GR
, while COUP-TFII formed a complex with GR, but not with GR, in an in vivo chromatin immunoprecipitation and a regular immunoprecipitation assay. Accordingly, GR, but not GR, enhanced COUP-TFII-induced transactivation of the simple COUP-TFII-responsive 7-hydroxylase promoter through the transcriptional activity of its activation function-1 (AF-1) domain, while COUP-TFII repressed GR-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors (SMRT). 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 (PEPCK), 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.
and •
yeast two-hybrid screening •
protein-protein interactions •
mouse mammary tumor virus (MMTV) •
phosphoenolpyruvate carboxykinase (PEPCK) •
cholesterol 7-hydroxylase (CYP7A) •
cytochrome p450 3A (CYP3A) •
gluconeogenesis
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