Division of Mathematical Science, Department of Systems Innovation, Graduate School of Engineering Science, Osaka University, Osaka, Japan.
Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
J Theor Biol. 2019 Feb 7;462:479-489. doi: 10.1016/j.jtbi.2018.11.023. Epub 2018 Nov 27.
The transcription factor NF-κB performs various cell functions, such as regulating proliferation and differentiation and blocking apoptosis, by inducing the expression of multiple genes. The shuttling of NF-κB between the cytoplasm and nucleus is involved in its transcriptional activity in the canonical NF-κB pathway. The transcription of the NF-κB target genes is regulated by the phosphorylation of both IκBα and the RelA subunit of NF-κB, suggesting that these phosphorylation events are crucial for the oscillation. In this study, we constructed a new mathematical model of NF-κB activation to explore the modulation of the oscillation by the phosphorylation of IκBα and RelA. Based on a stability analysis around the equilibrium point, we confirmed that IκBα phosphorylation added a structure with a stable periodic solution to the phosphorylation model. The stable periodic solution appeared to transiently respond to the attenuation of the concentration of active IKKβ. Because the NF-κB oscillation is caused by the periodic solution, the amplitude and period of the NF-κB oscillation in the phosphorylation model was constant regardless of the initial conditions; we defined this property as the reproducibility of the oscillation. On the other hand, the amplitude and period of the NF-κB oscillation depended on a parameter related to the RelA phosphorylation, suggesting that the oscillation period is regulated by RelA phosphorylation. In addition, the region of the periodic solution that is dependent on active IKKβ also depends on a parameter related to RelA phosphorylation. Therefore, we conclude that the phosphorylation of both IκBα and RelA regulates the robustness of the NF-κB signaling module oscillation. That is, by appropriately controlling the phosphorylation process, it becomes possible to control the NF-κB oscillation and appropriately induce the NFkB-dependent expression gene. We anticipate that this study will contribute to the future elucidation of the mechanism underlying the nuclear cytoplasmic (N-C) oscillation of NF-κB.
转录因子 NF-κB 通过诱导多种基因的表达来执行各种细胞功能，如调节增殖和分化以及阻止细胞凋亡。NF-κB 在细胞质和细胞核之间的穿梭参与了其在经典 NF-κB 途径中的转录活性。NF-κB 靶基因的转录受 IκBα 和 NF-κB 的 RelA 亚基的磷酸化调节，这表明这些磷酸化事件对振荡至关重要。在本研究中，我们构建了一个新的 NF-κB 激活数学模型，以探讨 IκBα 和 RelA 磷酸化对振荡的调制。基于平衡点周围的稳定性分析，我们证实 IκBα 磷酸化在磷酸化模型中添加了一个具有稳定周期解的结构。稳定的周期解似乎对活性 IKKβ 浓度的衰减有短暂的响应。由于 NF-κB 振荡是由周期解引起的，因此磷酸化模型中 NF-κB 振荡的幅度和周期与初始条件无关；我们将此特性定义为振荡的可重复性。另一方面，NF-κB 振荡的幅度和周期取决于与 RelA 磷酸化相关的参数，这表明振荡周期受 RelA 磷酸化的调节。此外，依赖于活性 IKKβ 的周期解的区域也取决于与 RelA 磷酸化相关的参数。因此，我们得出结论，IκBα 和 RelA 的磷酸化调节 NF-κB 信号模块振荡的稳健性。也就是说，通过适当控制磷酸化过程，可以控制 NF-κB 振荡并适当诱导 NFkB 依赖性表达基因。我们预计，这项研究将有助于阐明 NF-κB 的核质（N-C）振荡的机制。
