Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8568, Japan.
NPJ Syst Biol Appl. 2021 Dec 1;7(1):42. doi: 10.1038/s41540-021-00204-7.
Inflammatory stimuli triggers the degradation of three inhibitory κB (IκB) proteins, allowing for nuclear translocation of nuclear factor-κB (NFκB) for transcriptional induction of its target genes. Of these three, IκBα is a well-known negative feedback regulator that limits the duration of NFκB activity. We sought to determine whether IκBα's role in enabling or limiting NFκB activation is important for tumor necrosis factor (TNF)-induced gene expression in human breast cancer cells (MCF-7). Contrary to our expectations, many more TNF-response genes showed reduced induction than enhanced induction in IκBα knockdown cells. Mathematical modeling was used to investigate the underlying mechanism. We found that the reduced activation of some NFκB target genes in IκBα-deficient cells could be explained by the incoherent feedforward loop (IFFL) model. In addition, for a subset of genes, prolonged NFκB activity due to loss of negative feedback control did not prolong their transient activation; this implied a multi-state transcription cycle control of gene induction. Genes encoding key inflammation-related transcription factors, such as JUNB and KLF10, were found to be best represented by a model that contained both the IFFL and the transcription cycle motif. Our analysis sheds light on the regulatory strategies that safeguard inflammatory gene expression from overproduction and repositions the function of IκBα not only as a negative feedback regulator of NFκB but also as an enabler of NFκB-regulated stimulus-responsive inflammatory gene expression. This study indicates the complex involvement of IκBα in the inflammatory response to TNF that is induced by radiation therapy in breast cancer.
炎症刺激物触发三种抑制κB（IκB）蛋白的降解，使核因子-κB（NFκB）核转位，从而转录诱导其靶基因。在这三种蛋白中，IκBα是一种众所周知的负反馈调节剂，限制 NFκB 活性的持续时间。我们试图确定 IκBα在允许或限制 NFκB 激活方面对于肿瘤坏死因子（TNF）诱导的人类乳腺癌细胞（MCF-7）中的基因表达是否重要。与我们的预期相反，在 IκBα 敲低细胞中，许多 TNF 反应基因的诱导减少，而不是增加。数学建模被用来研究潜在的机制。我们发现，由于缺乏负反馈控制，一些 NFκB 靶基因在 IκBα 缺陷细胞中的激活减少，可以用非相干前馈环（IFFL）模型来解释。此外，对于一组基因，由于负反馈控制的丧失导致 NFκB 活性延长，但并没有延长它们的瞬时激活；这意味着基因诱导的转录循环控制是多态的。发现编码关键炎症相关转录因子的基因，如 JUNB 和 KLF10，最好用包含 IFFL 和转录循环基序的模型来表示。我们的分析揭示了保护炎症基因表达免受过度产生的调控策略，并重新定位了 IκBα 的功能，不仅作为 NFκB 的负反馈调节剂，而且作为 NFκB 调节的刺激反应性炎症基因表达的使能剂。这项研究表明，IκBα 在乳腺癌放射治疗诱导的 TNF 炎症反应中具有复杂的参与。
