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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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