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.
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.
De Martino
Massimo U
MU
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, MD 20892-1583, USA.
Bhattachryya
Nisan
N
Alesci
Salvatore
S
Ichijo
Takamasa
T
Chrousos
George P
GP
Kino
Tomoshige
T
D000818:Animals; D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D056985:Nuclear Receptor Co-Repressor 2; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D056985:Nuclear Receptor Co-Repressor 2; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D012097:Repressor Proteins; D014157:Transcription Factors; C539130:NCOR2 protein, human; C539132:Ncor2 protein, rat; C497588:Nr2f2 protein, rat; C095569:NR2F2 protein, human