A Small-Molecule Inducer of the Antioxidant Response Element
A Small-Molecule Inducer of the Antioxidant Response Element
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DOI：
10.1016/j.chembiol.2010.03.013
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发表时间：
2010-05-28
影响因子：
--
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
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作者：
Hur, Wooyoung;Sun, Zheng;Gray, Nathanael S.
真核细胞通过激活Nrf 2对抗氧化和其他环境应激，Nrf 2是一种转录因子，通过与抗氧化反应元件（ARE）结合来控制保护酶的表达。能够激活Nrf 2及其下游靶基因的亲电分子已在致癌物诱导的肿瘤模型中显示出治疗潜力。使用高通量细胞筛选，我们发现了一类ARE激活剂，我们将其命名为AI-1，它通过共价修饰Nrf 2的负调节因子Keap 1来激活Nrf 2。生物化学研究表明，AI-1修饰Keap 1的Cys 151破坏了Keap 1作为Cul 3-Keap 1泛素连接酶复合物接头的能力，从而引起Nrf 2的稳定和转录激活。Al-1及其生物素化衍生物是研究细胞抗氧化反应的分子细节的有用的药理学探针。
Eukaryotic cells counteract oxidative and other environmental stress through the activation of Nrf2, the transcription factor that controls the expression of a host of protective enzymes by binding to the antioxidant response element (ARE). The electrophilic molecules that are able to activate Nrf2 and its downstream target genes have demonstrated therapeutic potential in carcinogen-induced tumor models. Using a high-throughput cellular screen, we discovered a class of ARE activator, which we named AI-1, that activates Nrf2 by covalently modifying Keap1, the negative regulator of Nrf2. Biochemical studies indicated that modification of Cys151 of Keap1 by AI-1 disrupted the ability of Keap1 to serve as an adaptor for Cul3-Keap1 ubiquitin ligase complex, thereby causing stabilization and transcriptional activation of Nrf2. Al-1 and its biotinylated derivative are useful pharmacological probes for investigating the molecular details of the cellular antioxidant response.