Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
Mol Cells. 2023 Mar 31;46(3):133-141. doi: 10.14348/molcells.2023.0028. Epub 2023 Mar 27.
Transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. NRF2 induces expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. KEAP1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of CULLIN 3 (CUL3)-based E3 ubiquitin ligase. KEAP1 regulates the activity of NRF2 and acts as a sensor for oxidative and electrophilic stresses. NRF2 has been found to be activated in many types of cancers with poor prognosis. Therapeutic strategies to control NRF2-overeactivated cancers have been considered not only by targeting cancer cells with NRF2 inhibitors or NRF2 synthetic lethal chemicals, but also by targeting host defense with NRF2 inducers. Understanding precise molecular mechanisms how the KEAP1-NRF2 system senses and regulates the cellular response is critical to overcome intractable NRF2-activated cancers.
转录因子 NRF2（NF-E2 相关因子 2）是细胞应对环境应激的主要调节剂。NRF2 诱导解毒和抗氧化酶的表达，并抑制促炎细胞因子基因的诱导。KEAP1（Kelch-like ECH-associated protein 1）是 CUL3 基 E3 泛素连接酶的衔接子亚基。KEAP1 调节 NRF2 的活性，并作为氧化和亲电应激的传感器。已经发现 NRF2 在许多预后不良的癌症类型中被激活。控制 NRF2 过激活癌症的治疗策略不仅通过用 NRF2 抑制剂或 NRF2 合成致死化学物质靶向癌细胞，而且通过用 NRF2 诱导物靶向宿主防御来考虑。了解 KEAP1-NRF2 系统如何感知和调节细胞反应的精确分子机制对于克服难治性 NRF2 激活的癌症至关重要。
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