TAILIEUCHUNG - Báo cáo khoa học: Bridging the gap between in silico and cell-based analysis of the nuclear factor-jB signaling pathway by in vitro studies of IKK2

Previously, we have shown by sensitivity analysis, that the oscillatory behavior of nuclear factor (NF-jB) is coupled to free IkappaB kinase-2 (IKK2) and IkappaBalpha(IjBa), and that the phosphorylation of IjBaby IKK influences the amplitude of NF-jB oscillations. | ễFEBS Journal Bridging the gap between in silico and cell-based analysis of the nuclear factor-KB signaling pathway by in vitro studies of IKK2 Adaoha E. C. Ihekwaba1 4 Stephen J. Wilkinson1 Dominic Waithe3 David S. Broomhead2 Peter Li1 Rachel L. Grimley3 and Neil Benson3 1 Schoolof Chemistry The University of Manchester Faraday Building UK 2 Schoolof Mathematics The University of Manchester UK 3 Pfizer GlobalResearch and Development Sandwich UK 4 VBI Virginia Tech Blacksburg VA USA Keywords enzyme kinetics in silico in vitro nuclear factor-KB regulation signal transduction Correspondence A. E. C. Ihekwaba VBI Virginia Tech Washington Street Blacksburg VA USA Fax 1 540 2312606 Tel 1 540 2310795 E-mail ihekwaba@ Received 13 July 2006 revised 19 December 2006 accepted 22 January 2007 doi Previously we have shown by sensitivity analysis that the oscillatory behavior of nuclear factor NF-kB is coupled to free IkappaB kinase-2 IKK2 and IkappaBalpha IKBa and that the phosphorylation of IkBm by IKK influences the amplitude of NF-kB oscillations. We have performed further analyses of the behavior of NF-kB and its signal transduction network to understand the dynamics of this system. A time lapse study of NF-kB translocation in 10 000 cells showed discernible oscillations in levels of nuclear NF-kB amongst cells when stimulated with interleukin IL-1a which suggests a small degree of synchronization amongst the cell population. When the kinetics for the phosphorylation of IkBm by IKK were measured we found that the values for the affinity and catalytic efficiency of IKK2 for IkBm were dependent on assay conditions. The application of these kinetic parameters in our computational model of the NF-kB pathway resulted in significant differences in the oscillatory patterns of NF-kB depending on the rate constant value used. Hence interpretation of in silico models should be made in the context of this uncertainty. In silico analysis of .

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