Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway
Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway
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DOI：
10.1126/science.1069004
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发表时间：
2002-03-29
期刊：
影响因子：
56.9
通讯作者：
Finkel, T
中科院分区：
文献类型：
--
作者：
Nemoto, S;Finkel, T
长寿的遗传决定因素包括线虫中与叉头相关的转录因子DAF-16和小鼠中的p66shc基因座。我们证明了p66shc调节哺乳动物细胞内氧化剂的水平，而过氧化氢可以负向调节叉头的活性。在p66shc(-/-)细胞中，哺乳动物叉头同系物FKHRL1的活性增加，依赖于氧化还原的叉头失活减少。此外，FKHRL1的表达导致过氧化氢清除能力和氧化应激抵抗能力的增强。这些结果证明了与衰老相关的三个不同元素之间的重要功能关系：叉头蛋白、p66shc和细胞内氧化剂。
Genetic determinants of longevity include the forkhead-related transcription factor DAF-16 in the worm Caenorhabditis elegans and the p66shc locus in mice. We demonstrate that p66shc regulates intracellular oxidant levels in mammalian cells and that hydrogen peroxide can negatively regulate forkhead activity. In p66shc(-/-) cells, the activity of the mammalian forkhead homolog FKHRL1 is increased and redox-dependent forkhead inactivation is reduced. In addition, expression of FKHRL1 results in an increase in both hydrogen peroxide scavenging and oxidative stress resistance. These results demonstrate an important functional relation between three distinct elements linked to aging: forkhead proteins, p66shc, and intracellular oxidants.