Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress
Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress
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DOI：
10.1038/nature01036
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发表时间：
2002-09-19
期刊：
影响因子：
64.8
通讯作者：
Burgering, BMT
中科院分区：
文献类型：
--
作者：
Kops, GJPL;Dansen, TB;Burgering, BMT
活性氧是细胞增殖所必需的，但也可诱导细胞凋亡（1）。在增殖细胞中，这种矛盾通过蛋白激酶B（PKB;也称为c-Akt）的激活来解决，其保护细胞免于凋亡（2）。相反，缺乏PKB活性的静止细胞如何保护免受活性氧诱导的细胞死亡尚不清楚。在这里，我们表明PKB调节的Forkhead转录因子FOXO 3a（也称为FKHR-L1）通过直接增加锰超氧化物歧化酶（MnSOD）信使RNA和蛋白质的数量来保护静止细胞免受氧化应激。这种对活性氧的保护作用的增加拮抗了由葡萄糖剥夺引起的细胞凋亡。在缺乏PKB介导的信号传导的保护机制的静止细胞中，作为PKB失活的结果诱导了另一种机制。该机制需要Forkhead转录因子的激活，MnSOD的转录激活和随后的活性氧的减少。对氧化应激的抵抗力增加与长寿有关。叉头参与调节寿命的模型源于秀丽隐杆线虫的遗传分析（3-6），我们得出结论，该模型也扩展到哺乳动物系统。
Reactive oxygen species are required for cell proliferation but can also induce apoptosis(1). In proliferating cells this paradox is solved by the activation of protein kinase B (PKB; also known as c-Akt), which protects cells from apoptosis(2). By contrast, it is unknown how quiescent cells that lack PKB activity are protected against cell death induced by reactive oxygen species. Here we show that the PKB-regulated Forkhead transcription factor FOXO3a (also known as FKHR-L1) protects quiescent cells from oxidative stress by directly increasing their quantities of manganese superoxide dismutase (MnSOD) messenger RNA and protein. This increase in protection from reactive oxygen species antagonizes apoptosis caused by glucose deprivation. In quiescent cells that lack the protective mechanism of PKB-mediated signalling, an alternative mechanism is induced as a consequence of PKB inactivity. This mechanism entails the activation of Forkhead transcription factors, the transcriptional activation of MnSOD and the subsequent reduction of reactive oxygen species. Increased resistance to oxidative stress is associated with longevity. The model of Forkhead involvement in regulating longevity stems from genetic analysis in Caenorhabditis elegans(3-6), and we conclude that this model also extends to mammalian systems.