Motohashi Hozumi, Yamamoto Masayuki
Center for Tsukuba Advanced Research Alliance, Exploratory Research for Advanced Technology-Japan Science and Technology Corporation, University of Tsukuba, Tsukuba 305-8577, Japan.
Trends Mol Med. 2004 Nov;10(11):549-57. doi: 10.1016/j.molmed.2004.09.003.
The transcription factor Nrf2 regulates the basal and inducible expression of numerous detoxifying and antioxidant genes. The cytoplasmic protein Keap1 interacts with Nrf2 and represses its function. Analysis of keap1-knockout mice provides solid evidence that Keap1 acts as a negative regulator of Nrf2 and as a sensor of xenobiotic and oxidative stresses. The simultaneous ablation of the keap1 and nrf2 genes reversed all apparent phenotypes of the Keap1-deficient mice, suggesting that Nrf2 is a primary target of Keap1. The Nrf2-Keap1 system is now recognized as one of the major cellular defence mechanisms against oxidative and xenobiotic stresses. Furthermore, extensive studies have suggested that the Nrf2-Keap1 system contributes to protection against various pathologies, including carcinogenesis, liver toxicity, respiratory distress and inflammation.
转录因子Nrf2调节众多解毒和抗氧化基因的基础表达及诱导性表达。细胞质蛋白Keap1与Nrf2相互作用并抑制其功能。对Keap1基因敲除小鼠的分析提供了确凿证据，表明Keap1作为Nrf2的负调节因子以及外源性物质和氧化应激的传感器。Keap1和Nrf2基因的同时缺失逆转了Keap1缺陷小鼠的所有明显表型，表明Nrf2是Keap1的主要靶标。Nrf2-Keap1系统现在被认为是细胞对抗氧化和外源性应激的主要防御机制之一。此外，广泛的研究表明，Nrf2-Keap1系统有助于抵御各种病理状况，包括致癌作用、肝毒性、呼吸窘迫和炎症。
