The rise of antioxidant signaling-The evolution and hormetic actions of Nrf2
The rise of antioxidant signaling-The evolution and hormetic actions of Nrf2
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DOI：
10.1016/j.taap.2010.01.011
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Maher, Jonathan;Yamamoto, Masayuki
生物体已经进化出复杂和冗余的机制来管理内部代谢或外源性生存挑战引起的氧化和亲电子挑战。NF-E2相关因子2（Nrf 2）是一种转录因子，已经从原始起源进化了数千年，其同源物可追溯到无脊椎动物小杆线虫和果蝇物种。Nrf 2的祖先显然在造血中有着根深蒂固的根源，但已经多样化为一种转录因子，可以介导多种抗氧化信号和解毒基因。在高等生物中，通过富含半胱氨酸的Kelch样ECH相关蛋白1（Keap 1）引入了一种更复杂的严格调节Nrf 2活性的方法，从而表明需要调节Nrf 2活性。这在Keapl（-/-）小鼠中得到证实，其由于胃肠道角化过度而死于幼年死亡。尽管Nrf 2激活可保护免受急性毒性并预防或减轻几种疾病状态，但某些肿瘤中的组成性激活导致临床结果不佳，表明Nrf 2已响应于多种选择性压力而进化。本综述的目的是研究Nrf 2的起源，同时强调激活后引起的多功能性和保护能力。各种模型系统中，Nrf 2通常是有益的，但其中夸大的药理学加剧了生理或病理条件将得到解决。尽管达尔文原则已经基于环境和氧化挑战选择了Nrf 2活性以获得最大的有益效果，但是已经注意到亚生理学或超生理学效应都是有害的。因此，Nrf 2的功能表明了一种随时间经验性进化的兴奋因子。(C)2010年爱思唯尔公司All rights reserved.
Organisms have evolved sophisticated and redundant mechanisms to manage oxidative and electrophilic challenges that arise from internal metabolism or xenobiotic challenge for survival. NF-E2-related factor 2 (Nrf2) is a transcription factor that has evolved over millennia from primitive origins, with homologues traceable back to invertebrate Caenorhabditis and Drosophila species. The ancestry of Nrf2 clearly has deep-seated roots in hematopoiesis, yet has diversified into a transcription factor that can mediate a multitude of antioxidant signaling and detoxification genes. In higher organisms, a more sophisticated means of tightly regulating Nrf2 activity was introduced via the cysteine-rich kelch-like ECH-associated protein 1 (Keap1), thus suggesting a need to modulate Nrf2 activity. This is evidenced in Keapl(-/-) mice, which succumb to juvenile mortality due to hyperkeratosis of the gastrointestinal tract. Although Nrf2 activation protects against acute toxicity and prevents or attenuates several disease states, constitutive activation in some tumors leads to poor clinical outcomes, suggesting Nrf2 has evolved in response to a multitude of selective pressures. The purpose of this review is to examine the origins of Nrf2, while highlighting the versatility and protective abilities elicited upon activation. Various model systems in which Nrf2 is normally beneficial but in which exaggerated pharmacology exacerbates a physiological or pathological condition will be addressed. Although Darwinian principles have selected Nrf2 activity for maximal beneficial effect based on environmental and oxidative challenge, both sub- or super-physiological effects have been noted to be detrimental. The functions of Nrf2 thus suggest a hormetic factor that has evolved empirically over time. (C) 2010 Elsevier Inc. All rights reserved.