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Science 8 November 2002:
Vol. 298. no. 5596, pp. 1241 - 1245
DOI: 10.1126/science.1071914
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Reports

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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M. W. Covert, T. H. Leung, J. E. Gaston, and D. Baltimore (2005)
Science 309, 1854-1857
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Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of IKK Activity.
S. L. Werner, D. Barken, and A. Hoffmann (2005)
Science 309, 1857-1861
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Systems biology in the cell nucleus.
S. Gorski and T. Misteli (2005)
J. Cell Sci. 118, 4083-4092
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Cytokines and Sodium Induce Protein Kinase A-Dependent Cell-Surface Na,K-ATPase Recruitment via Dissociation of NF-{kappa}B/I{kappa}B/Protein Kinase A Catalytic Subunit Complex in Collecting Duct Principal Cells.
M. Vinciguerra, U. Hasler, D. Mordasini, M. Roussel, M. Capovilla, E. Ogier-Denis, A. Vandewalle, P.-Y. Martin, and E. Feraille (2005)
J. Am. Soc. Nephrol. 16, 2576-2585
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A Helminth Glycan Induces APC Maturation via Alternative NF-{kappa}B Activation Independent of I{kappa}B{alpha} Degradation.
P. G. Thomas, M. R. Carter, A. A. Da'dara, T. M. DeSimone, and D. A. Harn (2005)
J. Immunol. 175, 2082-2090
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Initiation and termination of NF-{kappa}B signaling by the intracellular protozoan parasite Toxoplasma gondii.
S. Shapira, O. S. Harb, J. Margarit, M. Matrajt, J. Han, A. Hoffmann, B. Freedman, M. J. May, D. S. Roos, and C. A. Hunter (2005)
J. Cell Sci. 118, 3501-3508
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FBI-1 Enhances Transcription of the Nuclear Factor-{kappa}B (NF-{kappa}B)-responsive E-selectin Gene by Nuclear Localization of the p65 Subunit of NF-{kappa}B.
D.-K. Lee, J.-E. Kang, H.-J. Park, M.-H. Kim, T.-H. Yim, J.-M. Kim, M.-K. Heo, K.-Y. Kim, H. J. Kwon, and M.-W. Hur (2005)
J. Biol. Chem. 280, 27783-27791
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Cardiac-specific blockade of NF-{kappa}B in cardiac pathophysiology: differences between acute and chronic stimuli in vivo.
M. Brown, M. McGuinness, T. Wright, X. Ren, Y. Wang, G. P. Boivin, H. Hahn, A. M. Feldman, and W. K. Jones (2005)
Am J Physiol Heart Circ Physiol 289, H466-H476
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