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Nat Immunol. 2014 Mar;15(3):239-47. doi: 10.1038/ni.2823. Epub 2014 Feb 2.

The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation.

Author information

1
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
2
Department of Hematology/Oncology, College of Medicine, University of Illinois, Chicago, Illinois, USA.
3
Department of Medicine, School of Medicine, University of California at San Francisco, San Francisco, California, USA.

Abstract

Here we found that the transcription repressor DREAM bound to the promoter of the gene encoding A20 to repress expression of this deubiquitinase that suppresses inflammatory NF-κB signaling. DREAM-deficient mice displayed persistent and unchecked A20 expression in response to endotoxin. DREAM functioned by transcriptionally repressing A20 through binding to downstream regulatory elements (DREs). In contrast, binding of the transcription factor USF1 to the DRE-associated E-box domain in the gene encoding A20 activated its expression in response to inflammatory stimuli. Our studies define the critical opposing functions of DREAM and USF1 in inhibiting and inducing A20 expression, respectively, and thereby the strength of NF-κB signaling. Targeting of DREAM to induce USF1-mediated A20 expression is therefore a potential anti-inflammatory strategy for the treatment of diseases associated with unconstrained NF-κB activity, such as acute lung injury.

PMID:
24487321
PMCID:
PMC4005385
DOI:
10.1038/ni.2823
[Indexed for MEDLINE]
Free PMC Article

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