The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation
The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation
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DOI：
10.1016/j.bcp.2012.11.016
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发表时间：
2013-03-15
影响因子：
5.8
通讯作者：
Park, B. Kevin
中科院分区：
文献类型：
--
作者：
Bryan, Holly K.;Olayanju, Adedamola;Park, B. Kevin
转录因子Nrf 2（NF-E2相关因子2）通过其调节大量抗氧化蛋白、解毒酶和异生素转运蛋白的基础和诱导表达的能力，在维持细胞稳态中起重要作用，特别是在细胞暴露于化学或氧化应激时。此外，Nrf 2有助于多种细胞功能，包括分化、增殖、炎症和脂质合成，并且Nrf 2的异常表达和/或功能与包括癌症、神经变性和心血管疾病在内的病理学的关联越来越大。Nrf 2的活性主要通过其与Keap 1（Kelch样ECH相关蛋白1）的相互作用来调节，Keap 1指导转录因子进行蛋白酶体降解。尽管人们普遍认为Keap 1中一个或多个关键半胱氨酸残基的修饰（例如化学加合、氧化、亚硝基化或谷胱甘肽化）可能是Nrf 2激活的化学生物学触发因素，但这种现象的明确证据仍然难以捉摸。越来越多的文献揭示了Nrf 2调节的替代机制，包括通过各种蛋白激酶（PKC，PI 3 K/Akt，GSK-3 β，JNK）磷酸化Nrf 2，与其他蛋白伴侣（p21，小窝蛋白-1）和表观遗传因子（micro-RNA-144，-28和-200 α，和启动子甲基化）的相互作用。这些和其他过程是Nrf 2活性的潜在重要决定因素，因此可能有助于维持细胞内稳态。在这里，我们解剖证据支持这些Keap 1依赖和独立的NRF 2调节机制。此外，我们强调在生物学的这一重要领域的关键知识差距，并建议这些可能是如何解决实验。(C)2012 Elsevier Inc. All rights reserved.
The transcription factor Nrf2 (NF-E2-related factor 2) plays a vital role in maintaining cellular homeostasis, especially upon the exposure of cells to chemical or oxidative stress, through its ability to regulate the basal and inducible expression of a multitude of antioxidant proteins, detoxification enzymes and xenobiotic transporters. In addition, Nrf2 contributes to diverse cellular functions including differentiation, proliferation, inflammation and lipid synthesis and there is an increasing association of aberrant expression and/or function of Nrf2 with pathologies including cancer, neurodegeneration and cardiovascular disease. The activity of Nrf2 is primarily regulated via its interaction with Keap1 (Kelch-like ECH-associated protein 1), which directs the transcription factor for proteasomal degradation. Although it is generally accepted that modification (e.g. chemical adduction, oxidation, nitrosylation or glutathionylation) of one or more critical cysteine residues in Keap1 represents a likely chemico-biological trigger for the activation of Nrf2, unequivocal evidence for such a phenomenon remains elusive. An increasing body of literature has revealed alternative mechanisms of Nrf2 regulation, including phosphorylation of Nrf2 by various protein kinases (PKC, PI3K/Akt, GSK-3 beta, JNK), interaction with other protein partners (p21, caveolin-1) and epigenetic factors (micro-RNAs -144, -28 and -200a, and promoter methylation). These and other processes are potentially important determinants of Nrf2 activity, and therefore may contribute to the maintenance of cellular homeostasis. Here, we dissect evidence supporting these Keap1-dependent and -independent mechanisms of Nrf2 regulation. Furthermore, we highlight key knowledge gaps in this important field of biology, and suggest how these may be addressed experimentally. (C) 2012 Elsevier Inc. All rights reserved.