Publication Date:
2002-11-09
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoffmann, Alexander -- Levchenko, Andre -- Scott, Martin L -- Baltimore, David -- New York, N.Y. -- Science. 2002 Nov 8;298(5596):1241-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12424381" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line
;
Cell Nucleus/metabolism
;
Chemokine CCL5/genetics
;
Chemokine CXCL10
;
Chemokines, CXC/genetics
;
Computer Simulation
;
Cytoplasm
;
DNA-Binding Proteins/genetics/*metabolism
;
Electrophoretic Mobility Shift Assay
;
Feedback, Physiological
;
*Gene Expression Regulation
;
Humans
;
I-kappa B Proteins/genetics/*metabolism
;
Mice
;
Mice, Knockout
;
Models, Biological
;
NF-kappa B/*metabolism
;
Proto-Oncogene Proteins/genetics/*metabolism
;
*Signal Transduction
;
Transcriptional Activation
;
Tumor Cells, Cultured
;
Tumor Necrosis Factor-alpha/metabolism/pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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