Affiliation:
1. Signaling Systems Laboratory, Department of Chemistry and Biochemistry, 9500 Gilman Drive, Mailcode 0375, La Jolla, CA 92093-0375, USA.
Abstract
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 IκB kinase (IKK), its substrate inhibitor of NF-κB (IκB), and the key inflammatory transcription factor NF-κB 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-α (TNFα)-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 TNFα depend on signaling pathway-specific mechanisms that regulate the temporal profile of IKK activity.
Publisher
American Association for the Advancement of Science (AAAS)
Cited by
429 articles.
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