Witt Johannes, Barisic Sandra, Schumann Eva, Allgöwer Frank, Sawodny Oliver, Sauter Thomas, Kulms Dagmar
Institute for System Dynamics, Universität Stuttgart, Pfaffenwaldring 9, 70569 Stuttgart, Germany.
BMC Syst Biol. 2009 Jul 16;3:71. doi: 10.1186/1752-0509-3-71.
Biological effects of nuclear factor-kappaB (NF kappaB) can differ tremendously depending on the cellular context. For example, NF kappaB induced by interleukin-1 (IL-1) is converted from an inhibitor of death receptor induced apoptosis into a promoter of ultraviolet-B radiation (UVB)-induced apoptosis. This conversion requires prolonged NF kappaB activation and is facilitated by IL-1 + UVB-induced abrogation of the negative feedback loop for NF kappaB, involving a lack of inhibitor of kappaB (I kappaB alpha) protein reappearance. Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha.
To investigate the mechanism underlying the general PP2A-mediated tuning of IKK beta phosphorylation upon IL-1 stimulation, we have developed a strictly reduced mathematical model based on ordinary differential equations which includes the essential processes concerning the IL-1 receptor, IKK beta and PP2A. Combining experimental and modelling approaches we demonstrate that constitutively active, but not post-stimulation activated PP2A, tunes out IKK beta phosphorylation thus allowing for I kappaB alpha resynthesis in response to IL-1. Identifiability analysis and determination of confidence intervals reveal that the model allows reliable predictions regarding the dynamics of PP2A deactivation and IKK beta phosphorylation. Additionally, scenario analysis is used to scrutinize several hypotheses regarding the mode of UVB-induced PP2Ac inhibition. The model suggests that down regulation of PP2Ac activity, which results in prevention of I kappaB alpha reappearance, is not a direct UVB action but requires instrumentality.
The model developed here can be used as a reliable building block of larger NF kappa B models and offers comprehensive simplification potential for future modeling of NF kappa B signaling. It gives more insight into the newly discovered mechanisms for IKK deactivation and allows for substantiated predictions and investigation of different hypotheses. The evidence of constitutive activity of PP2Ac at the IKK complex provides new insights into the feedback regulation of NF kappa B, which is crucial for the development of new anti-cancer strategies.
核因子-κB（NF-κB）的生物学效应在不同细胞环境中可能有极大差异。例如，白细胞介素-1（IL-1）诱导的NF-κB从死亡受体诱导的细胞凋亡抑制剂转变为紫外线B辐射（UVB）诱导的细胞凋亡促进剂。这种转变需要NF-κB的长时间激活，并且IL-1 + UVB诱导的NF-κB负反馈回路的废除会促进这种转变，这涉及κB抑制蛋白（IκBα）蛋白不再重新出现。UVB诱导的丝氨酸-苏氨酸磷酸酶PP2A（PP2Ac）催化亚基的抑制导致上游激酶IKKβ的永久激活，从而导致新合成的IκBα立即磷酸化和降解。
为了研究IL-1刺激后PP2A介导的IKKβ磷酸化一般调节机制，我们基于常微分方程开发了一个严格简化的数学模型，该模型包括与IL-1受体、IKKβ和PP2A相关的基本过程。结合实验和建模方法，我们证明组成型激活而非刺激后激活的PP2A可消除IKKβ磷酸化，从而允许响应IL-1重新合成IκBα。可识别性分析和置信区间的确定表明，该模型能够对PP2A失活和IKKβ磷酸化的动力学进行可靠预测。此外，情景分析用于审查关于UVB诱导的PP2Ac抑制模式的几种假设。该模型表明，导致IκBα不再重新出现的PP2Ac活性下调不是UVB的直接作用，而是需要媒介物。
这里开发的模型可作为更大的NF-κB模型的可靠构建模块，并为未来NF-κB信号传导建模提供全面的简化潜力。它更深入地了解了新发现的IKK失活机制，并允许进行有根据的预测和对不同假设的研究。PP2Ac在IKK复合物处的组成型活性证据为NF-κB的反馈调节提供了新见解，这对开发新的抗癌策略至关重要。
