Encoding NF-κB temporal control in response to TNF: distinct roles for the negative regulators IκBα and A20

Shannon L. Werner; Jeffrey D. Kearns; Victoria Zadorozhnaya; Candace Lynch; Ellen O’Dea; Mark P. Boldin; Averil Ma; David Baltimore; Alexander Hoffmann

doi:10.1101/gad.1680708

Encoding NF-κB temporal control in response to TNF: distinct roles for the negative regulators IκBα and A20

¹ Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093, USA;
² Division of Biology, California Institute of Technology, Pasadena, California 91125, USA;
³ Biomedical Sciences Division, University of California at San Francisco, San Francisco, California 94143, USA

↵4 These authors contributed equally to this work.

Abstract

TNF-induced NF-κB activity shows complex temporal regulation whose different phases lead to distinct gene expression programs. Combining experimental studies and mathematical modeling, we identify two temporal amplification steps—one determined by the obligate negative feedback regulator IκBα—that define the duration of the first phase of NF-κB activity. The second phase is defined by A20, whose inducible expression provides for a rheostat function by which other inflammatory stimuli can regulate TNF responses. Our results delineate the nonredundant functions implied by the knockout phenotypes of iκbα and a20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses.

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Footnotes

↵5 Present address: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
↵6 Corresponding author.

↵6 E-MAIL ahoffmann{at}ucsd.edu; FAX (858) 822-4671.
Supplemental material is available at http://www.genesdev.org.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1680708.
- Received April 2, 2008.
- Accepted June 16, 2008.