The glucocorticoid receptor is a co-regulator of the orphan nuclear receptor Nurr1.
Nurr1 (NR4A2) is an atypical nuclear receptor (NR) because of its inability to bind a ligand and to activate transcription following canonical NR rules. An affinity chromatography-based screen identified the glucocorticoid receptor (GR) as an interactant of Nurr1. The co-localization of these two NRs in the hippocampus and the substantia nigra, as well as their involvement in similar neurological processes led us to investigate the functional consequences of such a physical interaction. GR interfered with Nurr1 transcriptional activity, and Nurr1 association to GR confers glucocorticoid regulation to this orphan receptor. The N-terminal domain of Nurr1 interacts directly with GR, whereas several domains of GR can associate to Nurr1. The GR-mediated increase in Nurr1 transcriptional activity requires the N-terminal domain of GR, but not a functional DNA binding domain. Finally, SMRT and SRC2, two co-regulators of GR, modulated the transcriptional activity of the Nurr1-GR complex, but not that of Nurr1 alone. Our results therefore establish GR as a transcriptional regulator of Nurr1, and open new opportunities in the pharmacological regulation of Nurr1 by glucocorticoids in the CNS.
Carpentier
Rodolphe
R
Institut Pasteur de Lille, Lille, France.
Sacchetti
Paola
P
Ségard
Pascaline
P
Staels
Bart
B
Lefebvre
Philippe
P
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D016716:PC12 Cells; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D013378:Substantia Nigra; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000502:physiology*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C539131:Ncor2 protein, mouse; C539132:Ncor2 protein, rat; C539883:Nr4a2 protein, mouse; C539884:Nr4a2 protein, rat; D056985:Nuclear Receptor Co-Repressor 2; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; C486695:Sla2 protein, mouse; D014157:Transcription Factors; D016392:Proto-Oncogene Proteins pp60(c-src)