Abstract
TNF-induced NF-kappaB 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 IkappaBalpha-that define the duration of the first phase of NF-kappaB 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 ikappabalpha and a20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Line, Transformed
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Computer Simulation
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism*
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Dose-Response Relationship, Drug
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Embryo, Mammalian / cytology
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Feedback, Physiological
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Fibroblasts / metabolism
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mice
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Models, Theoretical
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Time Factors
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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I-kappa B Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Nfkbia protein, mouse
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Protein Isoforms
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Tumor Necrosis Factor alpha-Induced Protein 3
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Cysteine Endopeptidases
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Tnfaip3 protein, mouse