A systematic survey of the response of a model NF-κBκB signalling pathway to TNFαTNFα stimulation

Yunjiao Wang, Pawel Paszek, Caroline A. Horton, Hong Yue, Michael R.H. White, Douglas B. Kell, Mark R. Muldoon, David S. Broomhead

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Abstract

White's lab established that strong, continuous stimulation with tumour necrosis factor- (TNF ) can induce sustained oscillations in the subcellular localisation of the transcription factor nuclear factor B (NF- B). But the intensity of the TNF 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 TNF stimulation and the existence of sustained NF- B oscillations. Using a deterministic model developed by Ashall et al. in 2009, we find that the system's responses to TNF are characterised by a supercritical Hopf bifurcation point: above a critical intensity of TNF the system exhibits sustained oscillations in NF-kB localisation. For TNF 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 TNF 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- B mediated gene transcription.
Original languageEnglish
Pages (from-to)137-147
Number of pages11
JournalJournal of Theoretical Biology
Volume297
Early online date23 Dec 2011
DOIs
Publication statusPublished - 21 Mar 2012

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Keywords

  • gene transcription
  • subcellular localisation
  • computational bifurcation theory
  • bifurcation analysis
  • systematic survey
  • model nf-kappa b
  • signalling pathway
  • tnf alpha stimulation

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