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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}

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L. Zhang, M. Stanford, J. Liu, C. Barrett, L. Jiang, A. N. Barclay, and G. McFadden (2009)
J. Virol. 83, 9602-9607
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Multiple roles of the NF-{kappa}B signaling pathway regulated by coupled negative feedback circuits.
D. Kim, W. Kolch, and K.-H. Cho (2009)
FASEB J 23, 2796-2802
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NF-{kappa}B activity marks cells engaged in receptor editing.
E. J. Cadera, F. Wan, R. H. Amin, H. Nolla, M. J. Lenardo, and M. S. Schlissel (2009)
J. Exp. Med. 206, 1803-1816
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Dynamic Advances in NF-{kappa}B Signaling Analysis.
T. Kobayashi and R. Kageyama (2009)
Science Signaling 2, pe47
   Abstract »    Full Text »    PDF »
Kinetic control of negative feedback regulators of NF-{kappa}B/RelA determines their pathogen- and cytokine-receptor signaling specificity.
V. F.-S. Shih, J. D. Kearns, S. Basak, O. V. Savinova, G. Ghosh, and A. Hoffmann (2009)
PNAS 106, 9619-9624
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Pulsatile Stimulation Determines Timing and Specificity of NF-{kappa}B-Dependent Transcription.
L. Ashall, C. A. Horton, D. E. Nelson, P. Paszek, C. V. Harper, K. Sillitoe, S. Ryan, D. G. Spiller, J. F. Unitt, D. S. Broomhead, et al. (2009)
Science 324, 242-246
   Abstract »    Full Text »    PDF »
Annexin-1-deficient dendritic cells acquire a mature phenotype during differentiation.
A. Huggins, N. Paschalidis, R. J. Flower, M. Perretti, and F. D'Acquisto (2009)
FASEB J 23, 985-996
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A Small-Molecule Triptolide Suppresses Angiogenesis and Invasion of Human Anaplastic Thyroid Carcinoma Cells via Down-Regulation of the Nuclear Factor-{kappa}B Pathway.
W. Zhu, Y. Ou, Y. Li, R. Xiao, M. Shu, Y. Zhou, J. Xie, S. He, P. Qiu, and G. Yan (2009)
Mol. Pharmacol. 75, 812-819
   Abstract »    Full Text »    PDF »
Activated TNF-{alpha}/NF-{kappa}B signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice.
D. A. Altomare, C. W. Menges, J. Pei, L. Zhang, K. L. Skele-Stump, M. Carbone, A. B. Kane, and J. R. Testa (2009)
PNAS 106, 3420-3425
   Abstract »    Full Text »    PDF »
High Content Cell Screening in a Microfluidic Device.
R. Cheong, C. J. Wang, and A. Levchenko (2009)
Mol. Cell. Proteomics 8, 433-442
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Estrogen and Mechanisms of Vascular Protection.
D. Xing, S. Nozell, Y.-F. Chen, F. Hage, and S. Oparil (2009)
Arterioscler Thromb Vasc Biol 29, 289-295
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