Stimulus specificity of gene expression programs determined by temporal control of IKK activity.
|Title||Stimulus specificity of gene expression programs determined by temporal control of IKK activity.|
|Publication Type||Journal Article|
|Year of Publication||2005|
|Authors||Werner SL, Barken D, Hoffmann A|
|Date Published||2005 Sep 16|
|Keywords||Algorithms, 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.