Crosstalk between Nrf2 and Notch signaling.
Crosstalk between Nrf2 and Notch signaling.
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DOI：
10.1016/j.freeradbiomed.2015.05.017
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发表时间：
2015-11
影响因子：
7.4
通讯作者：
Kensler TW
中科院分区：
文献类型：
--
作者：
Wakabayashi N;Chartoumpekis DV;Kensler TW
转录因子Nrf 2（核因子，红细胞衍生2，like 2）属于CNC-bZip蛋白家族，与其直接异源二聚体伴侣sMaf和辅助因子（如CBP/p300）形成转录体。Nrf 2与位于数百个Nrf 2靶基因的基因调控区中的一个或多个ARE（抗氧化反应元件）结合。ARE是一种关键的增强子，其响应于内源性或外源性应激而被激活，以维持细胞和组织的稳态。来自基因表达微阵列分析的数据比较Nrf 2破坏和野生型小鼠胚胎成纤维细胞（MEF）显示，Notch 1和Notch信号相关基因的表达在Nrf 2破坏的细胞中降低。这一观察触发了我们对Nrf 2-Notch串扰的研究。一个功能性ARE已被确定上游的Notch 1主要转录起始位点。此外，在动物物种中，Rbpjκ结合位点在Nrf 2的启动子上是保守的。Notch 1是跨膜Notch家族受体之一，其与Rbpjκ转录因子一起驱动Notch信号传导。在典型地接受配体如Jags和Delta之后，受体经历裂解以产生易位到细胞核的Notch细胞内结构域。最近使用条件性基因敲除小鼠的研究表明，Notch 1和Notch 2在出生后的肝脏发育和肝功能的维持中发挥重要作用。在这篇综述中，我们总结了目前的理解之间的相互转录调节的作用Nrf 2和Notch在成人肝脏的研究使用Nrf 2，Keap 1和Notch 1基因工程小鼠。
The transcription factor, Nrf2 (nuclear factor, erythroid derived 2, like 2) belongs to the CNC-bZip protein family, forming a transcriptosome with its direct heterodimer partner, sMaf, and co-factors such as CBP/p300. Nrf2 binds to one or more ARE (Antioxidant Response Element) that are located in the gene regulatory regions of the hundreds of Nrf2 target genes. The ARE is a key enhancer that is activated in response to endogenous or exogenous stresses in order to maintain cellular and tissue homeostasis. Data emanating from gene expression microarray analyses comparing Nrf2-disrupted and wild-type mouse embryonic fibroblasts (MEF) showed that expression of Notch1 and Notch-signaling related genes were decreased in Nrf2-disrupted cells. This observation triggered our research on Nrf2-Notch crosstalk. A functional ARE has been identified upstream of the Notch1 major transcription start site. Furthermore, an Rbpjκ binding site is conserved on the promoters of Nrf2 among animal species. Notch1 is one of the transmembrane Notch family receptors, which drives Notch-signaling together with the Rbpjκ transcription factor. After canonically accepting ligands such as Jags and Deltas, the receptor undergoes cleavage to yield the Notch intracellular domain which translocates to the nucleus. Recent studies using conditional knockout mice indicate that Notch1 as well as Notch2 play important roles postnatally in liver development and in maintenance of hepatic function. In this review, we summarize current understanding of the role of reciprocal transcriptional regulation between Nrf2 and Notch in adult liver from studies using Nrf2, Keap1, and Notch1 genetically engineered mice.