IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells.
IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells.
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DOI：
10.1038/s41540-021-00204-7
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发表时间：
2021-12-01
影响因子：
4
通讯作者：
Okada M
中科院分区：
文献类型：
--
作者：
Ando M;Magi S;Seki M;Suzuki Y;Kasukawa T;Lefaudeux D;Hoffmann A;Okada M
炎症刺激触发三种抑制性κB（IκB）蛋白的降解，允许核因子-κB（NFκB）核转位以转录诱导其靶基因。在这三者中，IκBα是一种众所周知的负反馈调节剂，其限制NFκB活性的持续时间。我们试图确定IκBα在启动或限制NFκB活化中的作用是否对肿瘤坏死因子（TNF）诱导的人乳腺癌细胞（MCF-7）基因表达很重要。与我们的预期相反，在IκBα敲低细胞中，更多的TNF应答基因显示出诱导减少而不是诱导增强。数学模型被用来研究潜在的机制。我们发现IκBα缺陷细胞中某些NFκB B靶基因的激活降低可以用非相干前馈环（IFFL）模型来解释。此外，对于一个基因子集，由于负反馈控制的丧失而延长的NFκB活性并没有延长它们的瞬时激活;这意味着基因诱导的多状态转录周期控制。编码关键炎症相关转录因子的基因，如JUNB和KLF 10，被发现最好由包含IFFL和转录周期基序的模型代表。我们的分析揭示了保护炎症基因表达免于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NFκ B调节的刺激反应性炎症基因表达的启动子。这项研究表明IκBα在乳腺癌放疗诱导的TNF炎症反应中的复杂参与。
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.
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影响因子：
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通讯作者：
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