Stimulus specificity of gene expression programs determined by temporal control of IKK activity.
A small number of mammalian signaling pathways mediate a myriad of distinct physiological responses to diverse cellular stimuli. Temporal control of the signaling module that contains IkappaB kinase (IKK), its substrate inhibitor of NF-kappaB (IkappaB), and the key inflammatory transcription factor NF-kappaB can allow for selective gene activation. We have demonstrated that different inflammatory stimuli induce distinct IKK profiles, and we examined the underlying molecular mechanisms. Although tumor necrosis factor-alpha (TNFalpha)-induced IKK activity was rapidly attenuated by negative feedback, lipopolysaccharide (LPS) signaling and LPS-specific gene expression programs were dependent on a cytokine-mediated positive feedback mechanism. Thus, the distinct biological responses to LPS and TNFalpha depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.
Werner
Shannon L
SL
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, 9500 Gilman Drive, Mailcode 0375, La Jolla, CA 92093-0375, USA.
Barken
Derren
D
Hoffmann
Alexander
A
D000465:Algorithms; D000818:Animals; D019898:Autocrine Communication; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D016207:Cytokines / Q000235:genetics; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000172:deficiency / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology
D016207:Cytokines; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse