Journal
SCIENCE
Volume 309, Issue 5742, Pages 1857-1861Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1113319
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- NIGMS NIH HHS [GM72024, GM071573] Funding Source: Medline
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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 I kappa B kinase (IKK), its substrate inhibitor of NF-kappa B (I kappa B), and the key inflammatory transcription factor NF-kappa B 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 (TNF alpha)-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 TNF alpha depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.
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