title: Achieving stability of lipopolysaccharide-induced NF-kappaB activation.
abstract: The activation dynamics of the transcription factor NF-kappaB exhibit damped oscillatory behavior when cells are stimulated by tumor necrosis factor-alpha (TNFalpha) but stable behavior when stimulated by lipopolysaccharide (LPS). LPS binding to Toll-like receptor 4 (TLR4) causes activation of NF-kappaB that requires two downstream pathways, each of which when isolated exhibits damped oscillatory behavior. Computational modeling of the two TLR4-dependent signaling pathways suggests that one pathway requires a time delay to establish early anti-phase activation of NF-kappaB by the two pathways. The MyD88-independent pathway required Inferon regulatory factor 3-dependent expression of TNFalpha to activate NF-kappaB, and the time required for TNFalpha synthesis established the delay.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Covert
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Leung
authors.forename: Jahlionais E
authors.initials: JE
authors.lastname: Gaston
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000502:physiology; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050838:Interferon Regulatory Factor-3; D007700:Kinetics; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D003513:Cycloheximide; D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C000606205:Nfkbia protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse