Stimulus specificity of gene expression programs determined by temporal control of IKK activity.

TitleStimulus specificity of gene expression programs determined by temporal control of IKK activity.
Publication TypeJournal Article
Year of Publication2005
AuthorsWerner SL, Barken D, Hoffmann A
Date Published2005 Sep 16
KeywordsAlgorithms, Animals, Autocrine Communication, Cell Line, Cells, Cultured, Computer Simulation, Cytokines, Feedback, Physiological, Gene Expression Profiling, Gene Expression Regulation, I-kappa B Kinase, I-kappa B Proteins, Lipopolysaccharides, Mice, Models, Biological, NF-kappa B, Oligonucleotide Array Sequence Analysis, Protein-Serine-Threonine Kinases, Receptors, Immunologic, Signal Transduction, Toll-Like Receptor 4, Transcriptional Activation, Tumor Necrosis Factor-alpha

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.

PubMed URL
Alternate TitleScience
PubMed ID16166517