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PMID: 12529383 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment.

Molecular and cellular biology ·Vol. 23 ·No. 3 ·2003-02-00 ·Pages 763-76

Maira M, Martens C, Batsché E, Gauthier Y, Drouin J

Abstract

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.

MeSH Terms
Animals Base Sequence Binding Sites/genetics Cell Line Corticotropin-Releasing Hormone/metabolism Cyclic AMP/metabolism Cyclic AMP-Dependent Protein Kinases/metabolism DNA/genetics,metabolism DNA-Binding Proteins/chemistry,genetics,metabolism Dimerization Mice Models, Biological Nuclear Receptor Subfamily 4, Group A, Member 1 Pro-Opiomelanocortin/genetics Protein Structure, Tertiary Receptors, Cytoplasmic and Nuclear/chemistry,genetics,metabolism Receptors, Steroid Recombinant Proteins/chemistry,genetics,metabolism Signal Transduction Transcription Factors/chemistry,genetics,metabolism Transcription, Genetic
Chemicals
DNA-Binding Proteins Nr4a1 protein, mouse Nuclear Receptor Subfamily 4, Group A, Member 1 Receptors, Cytoplasmic and Nuclear Receptors, Steroid Recombinant Proteins Transcription Factors Pro-Opiomelanocortin DNA Corticotropin-Releasing Hormone Cyclic AMP Cyclic AMP-Dependent Protein Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Maira Mario
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.
Martens Christine
Batsché Eric
Gauthier Yves
Drouin Jacques
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.3.763-776.2003
Published
2003-02-00
Pages
763-76
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC140697
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.23.3.763-776.2003 PMC Full Text View journal details
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