Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor.
Glucocorticoids (Gc) act through the glucocorticoid receptor (GR) to enhance or repress transcription of glucocorticoid-responsive genes depending on the promoter and cellular context. Repression of proopiomelanocortin (POMC) gene expression by Gc was proposed to use different mechanisms. We described the POMC promoter Nur response element (NurRE) as a target for Gc repression. NGFI-B (Nur77), an orphan nuclear receptor, and two related factors, Nurr1 and NOR1, bind the NurRE as homo- or heterodimers to enhance POMC gene expression in response to CRH. Gc antagonize CRH-stimulated as well as NGFI-B-dependent transcription. We now show that GR antagonizes NurRE-dependent transcription induced by all members of the Nur77 subfamily and that these nuclear receptors can all interact directly with GR. Transcriptional antagonism as well as direct protein-protein interaction between NGFI-B and GR take place primarily via their respective DNA binding domains, although DNA binding itself and the GR homodimerization interface are not involved. In vivo, GR and Nur factors can be coimmunoprecipitated whereas GR is recruited to the POMC promoter upon glucocorticoid action. Thus, our data suggest a mechanism for transrepression between two nuclear receptors, GR and NGFI-B, that is unique, although quite similar to that proposed for transrepression between GR and activator protein 1 (AP-1) or nuclear factor-kappaB (NFkappaB).
Martens
Christine
C
Laboratoire de génétique moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montréal, Quebec, Canada H2W 1R7.
Bilodeau
Steve
S
Maira
Mario
M
Gauthier
Yves
Y
Drouin
Jacques
J
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015536:Down-Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D009154:Mutation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D012097:Repressor Proteins; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin