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Science 298 (5596): 1241-1245

Copyright © 2002 by the American Association for the Advancement of Science

The Ikappa B-NF-kappa B Signaling Module: Temporal Control and Selective Gene Activation

Alexander Hoffmann,1* Andre Levchenko,2* Martin L. Scott,3dagger David Baltimore1ddagger

Nuclear localization of the transcriptional activator NF-kappa B (nuclear factor kappa B) is controlled in mammalian cells by three isoforms of NF-kappa B inhibitor protein: Ikappa Balpha , -beta , and -epsilon . Based on simplifying reductions of the Ikappa B-NF-kappa B signaling module in knockout cell lines, we present a computational model that describes the temporal control of NF-kappa B activation by the coordinated degradation and synthesis of Ikappa B proteins. The model demonstrates that Ikappa Balpha is responsible for strong negative feedback that allows for a fast turn-off of the NF-kappa B response, whereas Ikappa Bbeta and -epsilon function to reduce the system's oscillatory potential and stabilize NF-kappa B responses during longer stimulations. Bimodal signal-processing characteristics with respect to stimulus duration are revealed by the model and are shown to generate specificity in gene expression.

1 Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
2 Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
3 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
*   These authors contributed equally to this work.

dagger    Present address: Biogen, Incorporated, Cambridge, MA 02142, USA.

ddagger    To whom correspondence should be addressed. E-mail: baltimo{at}caltech.edu

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G. R. Crabtree and I. A. Graef (2008)
Science Signaling 1, pe54
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Loss of Protein Kinase C{theta}, Bcl10, or Malt1 Selectively Impairs Proliferation and NF-{kappa}B Activation in the CD4+ T Cell Subset.
L. M. Kingeter and B. C. Schaefer (2008)
J. Immunol. 181, 6244-6254
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Dynamic Effect of Bortezomib on Nuclear Factor-{kappa}B Activity and Gene Expression in Tumor Cells.
M.-H. Sung, L. Bagain, Z. Chen, T. Karpova, X. Yang, C. Silvin, T. C. Voss, J. G. McNally, C. Van Waes, and G. L. Hager (2008)
Mol. Pharmacol. 74, 1215-1222
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Intron length increases oscillatory periods of gene expression in animal cells.
I. A. Swinburne, D. G. Miguez, D. Landgraf, and P. A. Silver (2008)
Genes & Dev. 22, 2342-2346
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Mapping global sensitivity of cellular network dynamics: sensitivity heat maps and a global summation law.
D.A Rand (2008)
J R Soc Interface 5, S59-S69
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Development of a Molecular Assay for Rapid Screening of Chemopreventive Compounds Targeting Nrf2.
Z. Wang, V. Gidwani, Z. Sun, D. D. Zhang, and P. K. Wong (2008)
Journal of Laboratory Automation 13, 243-248
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Encoding NF-{kappa}B temporal control in response to TNF: distinct roles for the negative regulators I{kappa}B{alpha} and A20.
S. L. Werner, J. D. Kearns, V. Zadorozhnaya, C. Lynch, E. O'Dea, M. P. Boldin, A. Ma, D. Baltimore, and A. Hoffmann (2008)
Genes & Dev. 22, 2093-2101
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Modulation of Gene Expression via Disruption of NF-{kappa}B Signaling by a Bacterial Small Molecule.
V. V. Kravchenko, G. F. Kaufmann, J. C. Mathison, D. A. Scott, A. Z. Katz, D. C. Grauer, M. Lehmann, M. M. Meijler, K. D. Janda, and R. J. Ulevitch (2008)
Science 321, 259-263
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Robust, Tunable Biological Oscillations from Interlinked Positive and Negative Feedback Loops.
T. Y.-C. Tsai, Y. S. Choi, W. Ma, J. R. Pomerening, C. Tang, and J. E. Ferrell Jr. (2008)
Science 321, 126-129
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Effect of Multiple Genetic Polymorphisms on Antigen Presentation and Susceptibility to Mycobacterium tuberculosis Infection.
S. T. Chang, J. J. Linderman, and D. E. Kirschner (2008)
Infect. Immun. 76, 3221-3232
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Requirements for Two Proximal NF-{kappa}B Binding Sites and I{kappa}B-{zeta} in IL-17A-induced Human {beta}-Defensin 2 Expression by Conducting Airway Epithelium.
C.-Y. Kao, C. Kim, F. Huang, and R. Wu (2008)
J. Biol. Chem. 283, 15309-15318
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Generation and Activation of Multiple Dimeric Transcription Factors within the NF-{kappa}B Signaling System.
S. Basak, V. F.-S. Shih, and A. Hoffmann (2008)
Mol. Cell. Biol. 28, 3139-3150
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Stabilization of RelB Requires Multidomain Interactions with p100/p52.
A. J. Fusco, O. V. Savinova, R. Talwar, J. D. Kearns, A. Hoffmann, and G. Ghosh (2008)
J. Biol. Chem. 283, 12324-12332
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Real-time analysis of gene regulation by glucocorticoid hormones.
A McMaster, T Chambers, Q-J Meng, S Grundy, A S I Loudon, R Donn, and D W Ray (2008)
J. Endocrinol. 197, 205-211
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