Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
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DOI：
10.1126/science.1094637
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发表时间：
2004-03-26
期刊：
影响因子：
56.9
通讯作者：
Greenberg, ME
中科院分区：
文献类型：
--
作者：
Brunet, A;Sweeney, LB;Greenberg, ME
Sir2脱乙酰基酶调节各种物种的生物体寿命。然而，Sir2增加寿命的分子机制在很大程度上是未知的。我们发现，在哺乳动物细胞中，Sir2同源SIRT1似乎通过调节FOXO家族的叉头转录因子来控制细胞对压力的反应，FOXO家族是一个蛋白质家族，作为胰岛素信号传导途径的传感器和生物体寿命的调节因子。SIRT1和FOXO转录因子FOXO3在细胞中形成复合物以响应氧化应激，并且SIRT1在体外和细胞内使FOXO3脱乙酰基。SIRT 1对FOXO 3功能有双重作用：SIRT 1增加FOXO 3诱导细胞周期停滞和抗氧化应激的能力，但抑制FOXO 3诱导细胞死亡的能力。因此，Sir2蛋白质家族成员增加生物体寿命的一种方式是使FOXO依赖性反应远离凋亡并朝向抗应激。
The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.