Lipniacki Tomasz, Paszek Pawel, Brasier A R Allan R, Luxon Bruce, Kimmel Marek
Institute of Fundamental Technological Research, Warsaw, Poland.
J Theor Biol. 2004 May 21;228(2):195-215. doi: 10.1016/j.jtbi.2004.01.001.
The two-feedback-loop regulatory module of nuclear factor kappaB (NF-kappaB) signaling pathway is modeled by means of ordinary differential equations. The constructed model involves two-compartment kinetics of the activators IkappaB (IKK) and NF-kappaB, the inhibitors A20 and IkappaBalpha, and their complexes. In resting cells, the unphosphorylated IkappaBalpha binds to NF-kappaB and sequesters it in an inactive form in the cytoplasm. In response to extracellular signals such as tumor necrosis factor or interleukin-1, IKK is transformed from its neutral form (IKKn) into its active form (IKKa), a form capable of phosphorylating IkappaBalpha, leading to IkappaBalpha degradation. Degradation of IkappaBalpha releases the main activator NF-kappaB, which then enters the nucleus and triggers transcription of the inhibitors and numerous other genes. The newly synthesized IkappaBalpha leads NF-kappaB out of the nucleus and sequesters it in the cytoplasm, while A20 inhibits IKK converting IKKa into the inactive form (IKKi), a form different from IKKn, no longer capable of phosphorylating IkappaBalpha. After parameter fitting, the proposed model is able to properly reproduce time behavior of all variables for which the data are available: NF-kappaB, cytoplasmic IkappaBalpha, A20 and IkappaBalpha mRNA transcripts, IKK and IKK catalytic activity in both wild-type and A20-deficient cells. The model allows detailed analysis of kinetics of the involved proteins and their complexes and gives the predictions of the possible responses of whole kinetics to the change in the level of a given activator or inhibitor.
核因子κB（NF-κB）信号通路的双反馈回路调节模块通过常微分方程进行建模。构建的模型涉及激活剂IκB（IKK）和NF-κB、抑制剂A20和IκBα及其复合物的两室动力学。在静息细胞中，未磷酸化的IκBα与NF-κB结合，并将其以无活性形式隔离在细胞质中。响应诸如肿瘤坏死因子或白细胞介素-1等细胞外信号，IKK从其中性形式（IKKn）转变为其活性形式（IKKa），一种能够磷酸化IκBα的形式，导致IκBα降解。IκBα的降解释放出主要激活剂NF-κB，然后NF-κB进入细胞核并触发抑制剂和许多其他基因的转录。新合成的IκBα将NF-κB带出细胞核并将其隔离在细胞质中，而A20抑制IKK将IKKa转化为无活性形式（IKKi），一种不同于IKKn的形式，不再能够磷酸化IκBα。经过参数拟合后，所提出的模型能够正确再现所有可用数据变量的时间行为：NF-κB、细胞质IκBα、A20和IκBα mRNA转录物、IKK以及野生型和A20缺陷型细胞中的IKK催化活性。该模型允许对所涉及蛋白质及其复合物的动力学进行详细分析，并给出整个动力学对给定激活剂或抑制剂水平变化可能反应的预测。
