Overview of redox regulation by Keap1-Nrf2 system in toxicology and cancer
Overview of redox regulation by Keap1-Nrf2 system in toxicology and cancer
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DOI：
10.1016/j.cotox.2016.10.001
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发表时间：
2016-12-01
影响因子：
4.6
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Suzuki, Mikiko;Otsuki, Akihito;Yamamoto, Masayuki
Keap1-Nrf2通路是一种细胞防御系统，分别针对来自活性氧（ROS）和亲电试剂的氧化应激和外源应激。Nrf2是激活一组细胞保护基因的关键转录因子，包括那些编码抗氧化和解毒酶的基因。Keap1是基于cullin3的E3连接酶的一个接头蛋白，它调节Nrf2的活性以应对这些胁迫。在非应激条件下，Keap1通过蛋白酶体途径组成性地降解Nrf2。Keap1通过Nrf2 Neh2结构域的DLGex和ETGE位点与Nrf2相互作用，对调控Nrf2降解至关重要。ROS和亲电试剂修饰Keap1的半胱氨酸残基，使Keap1的泛素E3连接酶活性失活，使Nrf2逃离Keap1介导的抑制，迁移到细胞核中，激活其靶基因的表达。氧化应激可引起许多疾病，与Keap1半胱氨酸残基或Keap1-Nrf2结合表面相互作用的Nrf2诱导剂有望成为治疗这些疾病的药物。另一方面，一些证据表明癌细胞劫持Keap1-Nrf2系统以获得对化疗和放疗的抗性。在许多癌症中观察到人类KEAP1和NRF2基因的体细胞突变，导致NRF2的组成性激活和不良预后。本文综述了Keap1-Nrf2功能的分子基础和药物发现。
The Keap1-Nrf2 pathway is a cellular defense system against oxidative and xenobiotic stresses derived from reactive oxygen species (ROS) and electrophiles, respectively. Nrf2 is a key transcription factor that activates a set of cytoprotective genes, including those encoding antioxidative and detoxifying enzymes. Keap1 is an adaptor protein of Cullin3-based E3 ligase, which regulates Nrf2 activity in response to these stresses. Under unstressed conditions, Keap1 constitutively degrades Nrf2 via the proteasome pathway. Keap1 interacts with Nrf2 through DLGex and ETGE sites in Nrf2 Neh2 domain, which is critical for regulation of Nrf2 degradation. ROS and electrophiles modify cysteine residues of Keap1 to inactivate the ubiquitin E3 ligase activity of Keap1, so that Nrf2 escapes from the Keap1-mediated repression, migrates into the nucleus, and activates expression of its target genes. As oxidative stresses give rise to many diseases, Nrf2 inducers that interact with Keap1 cysteine residues or Keap1-Nrf2 binding surface are expected as drugs against these diseases. On the other hand, several lines of evidence have showed that cancer cells hijack the Keap1-Nrf2 system to obtain resistance of chemo-and radiotherapies. Somatic mutations in human KEAP1 and NRF2 genes are observed in a number of cancers, resulting in constitutive activation of NRF2 and poor prognosis. In this review, we describe molecular basis underlying the Keap1-Nrf2 function and drug discovery.