Analysing the Role of UVB-Induced Translational Inhibition and PP2Ac Deactivation in NF-kappa B Signalling Using a Minimal Mathematical Model

作者：Witt Johannes^*; Konrath Fabian; Sawodny Oliver; Ederer Michael; Kulms Dagmar; Sauter Thomas

来源：PLos One, 2012, 7(7): e40274.

DOI：10.1371/journal.pone.0040274

Activation of nuclear factor kappa B (NF-kappa B) by interleukin-1 beta (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 I kappa B alpha. 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-kappa B 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 I kappa B alpha 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 independent data. Weak constitutive IKK beta phosphorylation is shown to be a decisive process in I kappa B alpha degradation induced by UVB stimulation alone, but irrelevant for (co-) stimulations with IL-1. In silico knockout experiments show that translational inhibition is predominantly responsible for lack of I kappa B alpha recurrence following IL-1+UVB stimulation. In case of UVB stimulation alone, cooperation of both processes causes the observed decrease of I kappa B alpha. This shows that the processes leading to activation of transcription factor NF-kappa B upon stimulation with ultraviolet B radiation with and without interleukin-1 costimulation are more complex than previously thought, involving both a cross talk of UVB induced translational inhibition and PP2Ac deactivation. The importance of each of the mechanisms depends on the specific cellular setting.

• 出版日期2012-7-18