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Science 309 (5742): 1857-1861

Copyright © 2005 by the American Association for the Advancement of Science

Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of IKK Activity

Shannon L. Werner,* Derren Barken,* Alexander Hoffmann{dagger}

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 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.

Signaling Systems Laboratory, Department of Chemistry and Biochemistry, 9500 Gilman Drive, Mailcode 0375, La Jolla, CA 92093-0375, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: ahoffmann{at}ucsd.edu


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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Post-induction, Stimulus-specific Regulation of Tumor Necrosis Factor mRNA Expression.
A. V. Tsytsykova, J. V. Falvo, M. Schmidt-Supprian, G. Courtois, D. Thanos, and A. E. Goldfeld (2007)
J. Biol. Chem. 282, 11629-11638
   Abstract »    Full Text »    PDF »
Differential Regulation of Cytokine Release and Leukocyte Migration by Lipopolysaccharide-Stimulated Primary Human Lung Alveolar Type II Epithelial Cells and Macrophages.
A. J. Thorley, P. A. Ford, M. A. Giembycz, P. Goldstraw, A. Young, and T. D. Tetley (2007)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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