Abstract：
The KEAP1-NRF2-ARE signaling pathway plays a central role in mediating the adaptive cellular stress response to oxidative and electrophilic chemicals. This canonical pathway has been extensively studied and reviewed in the past two decades, but rarely was it looked at from a quantitative signaling perspective. Signal amplification, i.e., ultrasensitivity, is crucially important for robust induction of antioxidant genes to appropriate levels that can adequately counteract the stresses. In this review article, we examined a number of well-known molecular events in the KEAP1-NRF2-ARE pathway from a quantitative perspective with a focus on how signal amplification can be achieved. We illustrated, by using a series of mathematical models, that redox-regulated protein sequestration, stabilization, translation, nuclear trafficking, DNA promoter binding, and transcriptional induction - which are embedded in the molecular network comprising KEAP1, NRF2, sMaf, p62, and BACH1 - may generate highly ultrasensitive NRF2 activation and antioxidant gene induction. The emergence and degree of ultrasensitivity depend on the strengths of protein-protein and protein-DNA interaction and protein abundances. A unique, quantitative understanding of signal amplification in the KEAP1-NRF2-ARE pathway will help to identify sensitive targets for the prevention and therapeutics of oxidative stress-related diseases and develop quantitative adverse outcome pathway models to facilitate the health risk assessment of oxidative chemicals.
摘要：
KEAP1-NRF2-ARE信号通路在介导对氧化和亲电化学物质的适应性细胞应激反应中起着核心作用。在过去的二十年中，这种规范途径得到了广泛的研究和回顾，但很少从定量信号的角度来看。信号放大,即，超敏,对于将抗氧化剂基因强大地诱导到可以充分抵消压力的适当水平至关重要。在这篇评论文章中，我们从定量的角度研究了KEAP1-NRF2-ARE通路中许多众所周知的分子事件,重点研究了如何实现信号放大.我们举例说明，通过使用一系列数学模型，氧化还原调节的蛋白质螯合，稳定,翻译,核贩运，DNA启动子结合，和转录诱导-嵌入在包含KEAP1，NRF2，sMaf，p62和BACH1-可能产生高度超灵敏的NRF2激活和抗氧化基因诱导。超敏感的出现和程度取决于蛋白质-蛋白质和蛋白质-DNA相互作用的强度以及蛋白质丰度。一个独特的，定量了解KEAP1-NRF2-ARE通路中的信号放大将有助于确定氧化应激相关疾病的预防和治疗的敏感靶点,并建立定量不良结局通路模型,以促进氧化化学物质的健康风险评估.
