Sensitivity Analysis of a Computational Model of the IKK–NF-κB–IκBα–A20 Signal Transduction Network
Abstract: The NF-κB signaling network plays an important role in many different compartments of the immune system during immune activation. Using a computational model of the NF-κB signaling network involving two negative regulators, IκBα and A20, we performed sensitivity analyses with three different sampling methods and present a ranking of the kinetic rate variables by the strength of their influence on the NF-κB signaling response. We also present a classification of temporal-response profiles of nuclear NF-κB concentration into six clusters, which can be regrouped to three biologically relevant clusters. Last, we constructed a reduced network of the IKK–NF-κB–IκBα–A20 signal transduction based on the ranking.
- 1 & . 2006. Circuitry of nuclear factor κB signaling. Immunol. Rev. 210: 171–186.
- 2 , , & . 2002. The IκB-NF-κB signaling module: temporal control and selective gene activation. Science 298: 1241–1245.
- 3 , & . 2005. Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science 309: 1857–1861.
- 4 , , , et al. 2000. Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 289: 2350–2354.
- 5 , , , et al. 2004. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5: 1052–1060.
- 6 , , , et al. 2004. Oscillations in NF-κB signaling control the dynamics of gene expression. Science 306: 704–708.
- 7 2003. Oscillatory expression of Hes1, p53, and NF-κB driven by transcriptional time delays. Curr. Biol. 13: 1409–1413.
- 8 2004. The strength of indecisiveness: oscillatory behavior for better cell fate determination. Science STKE 264: pe55–pe58.
- 9 , & . 2006. Minimal model of spiky oscillations in NF-κB signaling. Proc. Natl. Acad. Sci. 103: 10840–10845.
- 10 , , , et al. 2004. Mathematical model of NF-κB regulatory module. J. Theor. Biol. 228: 195–215.
- 11 , , , et al. 2006. Stochastic regulation in early immune response. Biophys. J. 90: 725–742.
- 12 , , , et al. 2004. Sensitivity analysis of parameters controlling oscillatory signaling in the NF-κB pathway. Syst. Biol. 1: 93–103.
- 13 , , , et al. 2005. Synergistic control of oscillations in the NF-κB signaling pathway. IEEE Proc. Syst. Biol. 152: 153–160.
- 14 , & . 1999. Orthogonal Arrays: Theory and Applications. Springer Series in Statistics. Springer-Verlag. New York .
- 15 & . 2004. A user's guide to Sandia's Latin Hypercube sampling software: LHS UNIX library/standalone version. SAND Report: 2004–2439.
- 16 1967. Some Methods for Classification and Analysis of Multivariate Observations. Proceedings of the 5th Berkeley Symposium on Mathematical Statistics and Probability. 1: 281–297. University of California Press. Berkeley , CA .