The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation.
Nuclear localization of the transcriptional activator NF-kappaB (nuclear factor kappaB) is controlled in mammalian cells by three isoforms of NF-kappaB inhibitor protein: IkappaBalpha, -beta, and - epsilon. Based on simplifying reductions of the IkappaB-NF-kappaB signaling module in knockout cell lines, we present a computational model that describes the temporal control of NF-kappaB activation by the coordinated degradation and synthesis of IkappaB proteins. The model demonstrates that IkappaBalpha is responsible for strong negative feedback that allows for a fast turn-off of the NF-kappaB response, whereas IkappaBbeta and - epsilon function to reduce the system's oscillatory potential and stabilize NF-kappaB responses during longer stimulations. Bimodal signal-processing characteristics with respect to stimulus duration are revealed by the model and are shown to generate specificity in gene expression.
Hoffmann
Alexander
A
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Levchenko
Andre
A
Scott
Martin L
ML
Baltimore
David
D
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics; D003198:Computer Simulation; D003593:Cytoplasm; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C105627:NFKBIE protein, human; C000606205:Nfkbia protein, mouse; C491366:Nfkbie protein, mouse; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha