analysing the role of uvb-induced translational inhibition and pp2ac deactivation in nf-κb signalling using a minimal mathematical model分析uvb-induced转化的作用抑制和pp2ac失活在nf-κb信号使用最小的数学模型.pdfVIP

Analysing the Role of UVB-Induced Translational Inhibition and PP2Ac Deactivation in NF-kB Signalling Using a Minimal Mathematical Model 1 1,2 1 1 2 Johannes Witt *, Fabian Konrath , Oliver Sawodny , Michael Ederer , Dagmar Kulms , Thomas Sauter1,3* 1 Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany, 2 Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany, 3 Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg Abstract Activation of nuclear factor kB (NF-kB) by interleukin-1b (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-kB dependent resynthesis of its own inhibitor IkBa. However, apoptosis induced by ultraviolet B radiation (UVB) is not attenuated, but significantly enhanced by co-stimulation with IL-1 in human epithelial cells. Under these conditions NF-kB remains constitutively active and turns into a pro-apoptotic factor by selectively repressing anti-apoptotic genes. Two different mechanisms have been separately proposed to explain UV- induced lack of IkBa recurrence: global translational inhibition as well as deactivation of the Ser/Thr phosphatase PP2Ac. Using mathematical modelling, we show that the systems behaviour requires a combination of both mechanisms, and we quantify their contribution in different settings. A mathematical model including both mechanisms is developed and fitted to various experimental data sets. A comparison of the model results and predictions with model variants lacking one of the mechanisms shows that both mechanisms are present in our experimental setting. The model is successfully validated by the prediction of