Document Detail

A nuclear receptor corepressor transcriptional checkpoint controlling activator protein 1-dependent gene networks required for macrophage activation.
MedLine Citation:
PMID:  15452344     Owner:  NLM     Status:  MEDLINE    
The nuclear receptor corepressor (NCoR) and the related factor known as silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) are essential components of multiprotein complexes that mediate active repression by unliganded nuclear receptors. Recent studies suggest that NCoR and SMRT can interact with and exert repressive effects on several other classes of DNA-binding transcription factors, but the physiological importance of these interactions has not been established. Here, investigation of endogenous transcriptional programs regulated by NCoR in macrophages reveals that NCoR acts as a transcriptional checkpoint for activator protein (AP)-1-dependent gene networks that regulate diverse biological processes including inflammation, cell migration, and collagen catabolism, with loss of NCoR, resulting in derepression of AP-1 target genes. The NCoR corepressor complex imposes an active block of exchange of c-Jun for c-Jun/c-Fos heterodimers, with targeted deletion of the c-Jun locus, resulting in loss of NCoR complexes from AP-1 target genes under basal conditions. The checkpoint function of NCoR is relieved by signal-dependent phosphorylation of c-Jun, which directs removal of NCoR/HDAC3/TBL1/TBLR1 complexes through recruitment of a specific ubiquitylation complex, as a prerequisite to the default binding of c-Jun/c-Fos heterodimers and transcriptional activation. The requirement for a checkpoint function to achieve the appropriate dynamic range of transcriptional responses to inflammatory signals is likely to be used by other signal-dependent transcription factors that regulate diverse homeostatic and developmental processes.
Sumito Ogawa; Jean Lozach; Kristen Jepsen; Dominique Sawka-Verhelle; Valentina Perissi; Roman Sasik; David W Rose; Randall S Johnson; Michael G Rosenfeld; Christopher K Glass
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-09-27
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  101     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-10-07     Completed Date:  2004-11-04     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14461-6     Citation Subset:  IM    
Department of Cellular and Molecular Medicine, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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MeSH Terms
Cells, Cultured
Genes, jun
Macrophage Activation / genetics,  physiology*
Mice, Knockout
Models, Biological
Nuclear Proteins / deficiency,  genetics,  metabolism*
Nuclear Receptor Co-Repressor 1
Recombinant Proteins / genetics,  metabolism
Repressor Proteins / genetics,  metabolism*
Signal Transduction
Transcription Factor AP-1 / genetics,  metabolism*
Transcription, Genetic
Grant Support
5R01 CA 52599/CA/NCI NIH HHS
Reg. No./Substance:
0/Ncor1 protein, mouse; 0/Nuclear Proteins; 0/Nuclear Receptor Co-Repressor 1; 0/Recombinant Proteins; 0/Repressor Proteins; 0/Transcription Factor AP-1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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