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

Mol Endocrinol. 2004 Apr;18(4):820-33. doi: 10.1210/me.2003-0341. Epub 2004 Jan 22.


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 GRalpha and its splicing variant GRbeta, whereas COUP-TFII formed a complex with GRalpha, but not with GRbeta, in an in vivo chromatin immunoprecipitation and a regular immunoprecipitation assay. Accordingly, GRalpha, but not GRbeta, enhanced COUP-TFII-induced transactivation of the simple COUP-TFII-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas COUP-TFII repressed GRalpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors. Importantly, mutual protein-protein interaction of GRalpha 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 GRalpha. These interactions influence the transcription of both COUP-TFII- and GRalpha-responsive target genes, seem to be promoter specific, and can be in either a positive or negative direction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COUP Transcription Factor II
  • COUP Transcription Factors
  • Cholesterol 7-alpha-Hydroxylase / biosynthesis
  • Cholesterol 7-alpha-Hydroxylase / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation / physiology*
  • Humans
  • Nuclear Receptor Co-Repressor 2
  • Phosphoenolpyruvate Carboxykinase (GTP) / biosynthesis
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Rats
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism*
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • COUP Transcription Factor II
  • COUP Transcription Factors
  • DNA-Binding Proteins
  • NCOR2 protein, human
  • NR2F2 protein, human
  • Ncor2 protein, rat
  • Nr2f2 protein, rat
  • Nuclear Receptor Co-Repressor 2
  • Receptors, Glucocorticoid
  • Receptors, Steroid
  • Repressor Proteins
  • Transcription Factors
  • Cholesterol 7-alpha-Hydroxylase
  • Phosphoenolpyruvate Carboxykinase (GTP)