Ihekwaba Adaoha E C, Wilkinson Stephen J, Waithe Dominic, Broomhead David S, Li Peter, Grimley Rachel L, Benson Neil
School of Chemistry, The University of Manchester, Faraday Building, UK.
FEBS J. 2007 Apr;274(7):1678-90. doi: 10.1111/j.1742-4658.2007.05713.x. Epub 2007 Feb 20.
Previously, we have shown by sensitivity analysis, that the oscillatory behavior of nuclear factor (NF-kappaB) is coupled to free IkappaB kinase-2 (IKK2) and IkappaBalpha(IkappaBalpha), and that the phosphorylation of IkappaBalpha by IKK influences the amplitude of NF-kappaB oscillations. We have performed further analyses of the behavior of NF-kappaB and its signal transduction network to understand the dynamics of this system. A time lapse study of NF-kappaB translocation in 10,000 cells showed discernible oscillations in levels of nuclear NF-kappaB amongst cells when stimulated with interleukin (IL-1alpha), which suggests a small degree of synchronization amongst the cell population. When the kinetics for the phosphorylation of IkappaBalpha by IKK were measured, we found that the values for the affinity and catalytic efficiency of IKK2 for IkappaBalpha were dependent on assay conditions. The application of these kinetic parameters in our computational model of the NF-kappaB pathway resulted in significant differences in the oscillatory patterns of NF-kappaB depending on the rate constant value used. Hence, interpretation of in silico models should be made in the context of this uncertainty.
此前，我们通过敏感性分析表明，核因子（NF-κB）的振荡行为与游离的IκB激酶-2（IKK2）和IκBα相关，并且IKK对IκBα的磷酸化影响NF-κB振荡的幅度。我们对NF-κB及其信号转导网络的行为进行了进一步分析，以了解该系统的动力学。对10000个细胞中NF-κB易位的延时研究表明，在用白细胞介素（IL-1α）刺激时，细胞间核NF-κB水平存在明显的振荡，这表明细胞群体之间存在一定程度的同步性。当测量IKK对IκBα磷酸化的动力学时，我们发现IKK2对IκBα的亲和力和催化效率值取决于检测条件。在我们的NF-κB途径计算模型中应用这些动力学参数，根据所使用的速率常数不同，NF-κB的振荡模式会产生显著差异。因此，应在这种不确定性的背景下对计算机模拟模型进行解释。
