Encoding NF-kappaB temporal control in response to TNF: distinct roles for the negative regulators IkappaBalpha and A20.
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.
Werner
Shannon L
SL
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093, USA.
Kearns
Jeffrey D
JD
Zadorozhnaya
Victoria
V
Lynch
Candace
C
O'Dea
Ellen
E
Boldin
Mark P
MP
Ma
Averil
A
Baltimore
David
D
Hoffmann
Alexander
A
D000818:Animals; D002461:Cell Line, Transformed; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008962:Models, Theoretical; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse