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Molecular and Cellular Biology, February 2003, p. 763-776, Vol. 23, No. 3
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.3.763-776.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Dimer-Specific Potentiation of NGFI-B (Nur77) Transcriptional Activity by the Protein Kinase A Pathway and AF-1-Dependent Coactivator Recruitment

Mario Maira,1,2 Christine Martens,1,2 Éric Batsché,1 Yves Gauthier,1 and Jacques Drouin1,2*

Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, Québec, Canada H2W 1R7,1 Département de Biochimie, Université de Montréal, Montréal, Québec, Canada H3C 3J72

Received 17 May 2002/ Returned for modification 11 July 2002/ Accepted 29 October 2002

The NGFI-B (Nur77) subfamily of orphan nuclear receptors (NRs), which also includes Nurr1 and NOR1, bind the NurRE regulatory element as either homo- or heterodimers formed between subfamily members. These NRs mediate the activation of pituitary proopiomelanocortin (POMC) gene transcription by the hypothalamic hormone corticotropin-releasing hormone (CRH), an important link between neuronal and endocrine components of the hypothalamo-pituitary-adrenal axis. CRH effects on POMC transcription do not require de novo protein synthesis. We now show that CRH signals activate Nur factors through the cyclic AMP/protein kinase A (PKA) pathway. CRH and PKA rapidly increase nuclear DNA binding activity of NGFI-B dimers but not monomers. Accordingly, CRH- or PKA-activated Nur factors enhance dimer (but not monomer) target response elements. We also show that p160/SRC coactivators are recruited to Nur dimers (but not to monomers) and that coactivator recruitment to the NurRE is enhanced in response to CRH. Moreover, PKA- and coactivator-induced potentiation of NGFI-B activity are primarily exerted through the N-terminal AF-1 domain of NGFI-B. The TIF2 (SRC-2) glutamine-rich domain is required for this activity. Taken together, these results indicate that Nur factors behave as endpoint effectors of the PKA signaling pathway acting through dimers and AF-1-dependent recruitment of coactivators.

* Corresponding author. Mailing address: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), 110 des Pins Ouest, Montréal, Québec, Canada H2W 1R7. Phone: (514) 987-5680. Fax: (514) 987-5575. E-mail: drouinj{at}ircm.qc.ca.

Molecular and Cellular Biology, February 2003, p. 763-776, Vol. 23, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.3.763-776.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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