Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level.
Ectodermal-neural cortex 1 down-regulates Nrf2 at the translational level.
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DOI：
10.1371/journal.pone.0005492
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Zhang DD
中科院分区：
文献类型：
--
作者：
Wang XJ;Zhang DD
转录因子Nrf 2是针对环境损伤的细胞防御机制的主要调节因子。Nrf 2介导的抗氧化反应是通过转录一系列基因来完成的，这些基因编码II期解毒酶、异生物质转运蛋白和抗氧化剂。这些基因的协调表达在保护细胞免受毒性和致癌性损伤以及维持细胞氧化还原稳态方面至关重要。Nrf 2通路的激活主要由Kelch样ECH相关蛋白1（Keap 1）控制，Keap 1是根据细胞内氧化还原条件打开或关闭Nrf 2信号通路的分子开关。在这里，我们报告了我们发现的一种新的Nrf 2抑制外胚层神经皮层1（ENC 1），这是一种BTB-Kelch蛋白，属于同一家族的Keap 1。ENC 1的瞬时表达降低了Nrf 2及其下游基因表达的稳态水平。虽然ENC 1与Keap 1间接相互作用，但ENC 1介导的Nrf 2下调不依赖于Keap 1。ENC 1对Nrf 2的负面影响不是由于Nrf 2稳定性的变化，因为蛋白酶体和溶酶体抑制剂都没有任何影响。ENC 1的过表达并没有导致Nrf 2 mRNA水平的变化，而是导致Nrf 2蛋白合成速率的降低。这些结果表明，ENC 1通过抑制Nrf 2蛋白翻译作为Nrf 2的负调控因子发挥作用，这增加了控制Nrf 2信号通路的另一个复杂性水平。
The transcription factor Nrf2 is the master regulator of a cellular defense mechanism against environmental insults. The Nrf2-mediated antioxidant response is accomplished by the transcription of a battery of genes that encode phase II detoxifying enzymes, xenobiotic transporters, and antioxidants. Coordinated expression of these genes is critical in protecting cells from toxic and carcinogenic insults and in maintaining cellular redox homeostasis. Activation of the Nrf2 pathway is primarily controlled by Kelch-like ECH-associated protein 1 (Keap1), which is a molecular switch that turns on or off the Nrf2 signaling pathway according to intracellular redox conditions. Here we report our finding of a novel Nrf2 suppressor ectodermal-neural cortex 1 (ENC1), which is a BTB-Kelch protein and belongs to the same family as Keap1. Transient expression of ENC1 reduced steady-state levels of Nrf2 and its downstream gene expression. Although ENC1 interacted with Keap1 indirectly, the ENC1-mediated down-regulation of Nrf2 was independent of Keap1. The negative effect of ENC1 on Nrf2 was not due to a change in the stability of Nrf2 because neither proteasomal nor lysosomal inhibitors had any effects. Overexpression of ENC1 did not result in a change in the level of Nrf2 mRNA, rather, it caused a decrease in the rate of Nrf2 protein synthesis. These results demonstrate that ENC1 functions as a negative regulator of Nrf2 through suppressing Nrf2 protein translation, which adds another level of complexity in controlling the Nrf2 signaling pathway.
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DOI：
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