Abstract
Nuclear localization of the transcriptional activator NF-kappaB (nuclear factor kappaB) is controlled in mammalian cells by three isoforms of NF-kappaB inhibitor protein: IkappaBalpha, -beta, and - epsilon. Based on simplifying reductions of the IkappaB-NF-kappaB signaling module in knockout cell lines, we present a computational model that describes the temporal control of NF-kappaB activation by the coordinated degradation and synthesis of IkappaB proteins. The model demonstrates that IkappaBalpha is responsible for strong negative feedback that allows for a fast turn-off of the NF-kappaB response, whereas IkappaBbeta and - epsilon function to reduce the system's oscillatory potential and stabilize NF-kappaB 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cell Nucleus / metabolism
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Chemokine CCL5 / genetics
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Chemokine CXCL10
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Chemokines, CXC / genetics
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Computer Simulation
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Cytoplasm
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Electrophoretic Mobility Shift Assay
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Feedback, Physiological
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Gene Expression Regulation*
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Humans
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism*
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Mice
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Mice, Knockout
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Models, Biological
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Signal Transduction*
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Transcriptional Activation
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Chemokine CCL5
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Chemokine CXCL10
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Chemokines, CXC
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DNA-Binding Proteins
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I kappa B beta protein
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I-kappa B Proteins
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NF-kappa B
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NFKBIA protein, human
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NFKBIE protein, human
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Nfkbia protein, mouse
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Nfkbie protein, mouse
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Proto-Oncogene Proteins
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha