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J Theor Biol. 2012 Mar 21;297:137-47. doi: 10.1016/j.jtbi.2011.12.014. Epub 2011 Dec 23.

A systematic survey of the response of a model NF-κB signalling pathway to TNFα stimulation.

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1
Manchester Interdisciplinary Biocentre, University of Manchester, Manchester M1 7DN, UK. dekangxu@yahoo.com

Abstract

White's lab established that strong, continuous stimulation with tumour necrosis factor-α (TNFα) can induce sustained oscillations in the subcellular localisation of the transcription factor nuclear factor κB (NF-κB). But the intensity of the TNFα signal varies substantially, from picomolar in the blood plasma of healthy organisms to nanomolar in diseased states. We report on a systematic survey using computational bifurcation theory to explore the relationship between the intensity of TNFα stimulation and the existence of sustained NF-κB oscillations. Using a deterministic model developed by Ashall et al. in 2009, we find that the system's responses to TNFα are characterised by a supercritical Hopf bifurcation point: above a critical intensity of TNFα the system exhibits sustained oscillations in NF-kB localisation. For TNFα below this critical value, damped oscillations are observed. This picture depends, however, on the values of the model's other parameters. When the values of certain reaction rates are altered the response of the signalling pathway to TNFα stimulation changes: in addition to the sustained oscillations induced by high-dose stimulation, a second oscillatory regime appears at much lower doses. Finally, we define scores to quantify the sensitivity of the dynamics of the system to variation in its parameters and use these scores to establish that the qualitative dynamics are most sensitive to the details of NF-κB mediated gene transcription.

PMID:
22202812
PMCID:
PMC3315024
DOI:
10.1016/j.jtbi.2011.12.014
[Indexed for MEDLINE]
Free PMC Article
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