Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
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DOI：
10.1101/gad.13.1.76
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发表时间：
1999-01-01
影响因子：
10.5
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
转录因子Nrf2对于抗氧化反应元件（ARE）介导的II相解毒酶和氧化应激酶基因的诱导至关重要。对转染细胞系中所显示的不同Nrf2活性的详细分析最终导致了一种新蛋白质的鉴定，我们将其命名为Keap1，它通过与Nrf2进化上保守的氨基末端调节结构域特异性结合来抑制Nrf2的转录活性。Keap1最接近的同源物是一种果蝇肌动蛋白结合蛋白，称为Reich，这意味着Keap1可能是Nrf2的一种细胞质效应物。然后我们表明，亲电试剂在体内拮抗Keap1对Nrf2活性的抑制，使Nrf2能够从细胞质转移到细胞核并增强ARE反应。我们推测Keap1和Nrf2构成了一种对氧化应激至关重要的细胞传感器，并共同介导了通过这种新的Nrf2核穿梭机制导致转录激活的信号通路中的一个关键步骤。Nrf2的激活反过来又导致II相酶和抗氧化应激基因在对亲电试剂和活性氧物质的应答中被诱导。
Transcription factor Nrf2 is essential for the antioxidant responsive element (ARE)-mediated induction of phase LI detoxifying and oxidative stress enzyme genes. Detailed analysis of differential Nrf2 activity displayed in transfected cell lines ultimately led to the identification of a new protein, which we named Keap1, that suppresses Nrf2 transcriptional activity by specific binding to its evolutionarily conserved amino-terminal regulatory domain. The closest homolog of Keap1 is a Drosophila actin-binding protein called Reich, implying that Keap1 might be a Nrf2 cytoplasmic effector. We then showed that electrophilic agents antagonize Keap1 inhibition of Nrf2 activity in vivo, allowing Nrf2 to traverse from the cytoplasm to the nucleus and potentiate the ARE response. We postulate that Keap1 and Nrf2 constitute a crucial cellular sensor for oxidative stress, and together mediate a key step in the signaling pathway that leads to transcriptional activation by this novel Nrf2 nuclear shuttling mechanism. The activation of Nrf2 leads in turn to the induction of phase II enzyme and antioxidative stress genes in response to electrophiles and reactive oxygen species.