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

Genes and Development - Tập 22 Số 15 - Trang 2093-2101 - 2008
Shannon L. Werner1, Jeffrey D. Kearns, Victoria Zadorozhnaya, Candace Lynch, Ellen L O'Dea, Mark P. Boldin, Averil Ma, David Baltimore, Alexander Hoffmann
1Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093, USA.

Tóm tắt

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 ofiκbαanda20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses.

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Genes and Development

Tập 22 Số 15

2093-2101

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