Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1
Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1
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DOI：
10.1128/mcb.01591-09
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发表时间：
2010-06-15
影响因子：
5.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Taguchi, Keiko;Maher, Jonathan M.;Yamamoto, Masayuki
Keap1 调节 Nrf2 活性以应对异生素和氧化应激。 Nrf2 是细胞保护基因的重要调节因子。 Keap1缺失小鼠由于上消化道严重角化过度导致营养不良，在断奶时会致命。对Keap1::Nrf2双突变小鼠的分析表明，目前可识别的Keap1缺失小鼠的表型均归因于Nrf2的组成型激活。我们之前报道过肝细胞特异性 Keap1 敲除 (Keap1(flox/-)::Albumin-Cre) 小鼠具有存活能力，并且对对乙酰氨基酚 (APAP) 的急性毒性具有更强的抵抗力。在当前的研究中，我们发现 floxed Keap1 等位基因是低等位基因，并且 Keap1(flox/-) 小鼠的所有检查组织中 Keap1 表达均降低。利用 Keap1(flox/-) 小鼠的亚等位性表型，我们检查了成年小鼠中 Keap1 表达逐渐减少的效果。当受到 APAP 攻击时，Keap1(flox/-) 小鼠比野生型甚至 Keap1(flox/-)::Albumin-Cre 小鼠更能避免死亡。相比之下，在一项针对 2 岁小鼠的研究中，Keap1 水平降低至 50% 以下会导致死亡率增加。这些结果支持我们的观点，即 Nrf2 激活在急性毒性中的益处是毒效效应的，并且超过一定阈值的组成型 Nrf2 激活对长期生存相当不利。
Keap1 regulates Nrf2 activity in response to xenobiotic and oxidative stresses. Nrf2 is an essential regulator of cytoprotective genes. Keap1-null mice are lethal by weaning age due to malnutrition caused by severe hyperkeratosis of the upper digestive tract. Analysis of Keap1:: Nrf2 double mutant mice revealed that currently recognizable phenotypes of Keap1-null mice are all attributable to constitutive activation of Nrf2. We previously reported that hepatocyte-specific Keap1 knockout (Keap1(flox/-)::Albumin-Cre) mice are viable and more resistant to acute toxicity of acetaminophen (APAP). In the current study, we found that the floxed Keap1 allele is hypomorphic and that Keap1 expression was decreased in all examined tissues of Keap1(flox/-) mice. Taking advantage of the hypomorphic phenotype of Keap1(flox/-) mice, we examined the effects of graded reduction of Keap1 expression in adult mice. When challenged with APAP, Keap1(flox/-) mice were more protected from mortality than wild-type and even Keap1(flox/-)::Albumin-Cre mice. In contrast, a decrease in Keap1 levels to less than 50% resulted in increased mortality in a study of 2-year-old mice. These results support our contention that the benefits of Nrf2 activation in acute toxicity are hormetic and that constitutive Nrf2 activation beyond a certain threshold is rather disadvantageous to long-term survival.