The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor
The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor
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DOI：
10.1074/jbc.m705325200
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发表时间：
2007-10-12
影响因子：
4.8
通讯作者：
Brunet, Anne
中科院分区：
文献类型：
--
作者：
Greer, Eric L.;Oskoui, Philip R.;Brunet, Anne
在生物体的整个生命周期中维持体内平衡需要不断适应能量水平的变化。AMP激活的蛋白激酶（AMPK）通过关闭能量消耗途径和打开能量产生途径在细胞对低能量水平的反应中起关键作用。然而，AMPK调节细胞能量水平的转录机制还没有完全确定。在这里，我们发现AMPK直接调节哺乳动物FOXO 3，FOXO家族的Forkhead转录因子的成员，已知促进抗氧化应激，肿瘤抑制和长寿。我们发现AMPK磷酸化人FOXO 3在6个以前未确定的监管网站。AMPK的磷酸化导致FOXO 3转录活性的激活，而不影响FOXO 3的亚细胞定位。使用全基因组微阵列分析，我们确定了一组靶基因，在哺乳动物细胞中的这六个调控位点磷酸化时，由FOXO 3调控。AMPK对FOXO 3的调节可能在微调基因表达程序中起着至关重要的作用，这些基因表达程序控制着细胞在整个生命过程中的能量平衡和抗应激能力。
The maintenance of homeostasis throughout an organism's life span requires constant adaptation to changes in energy levels. The AMP-activated protein kinase ( AMPK) plays a critical role in the cellular responses to low energy levels by switching off energy-consuming pathways and switching on energy-producing pathways. However, the transcriptional mechanisms by which AMPK acts to adjust cellular energy levels are not entirely characterized. Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites. Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. Using a genome-wide microarray analysis, we identify a set of target genes that are regulated by FOXO3 when phosphorylated at these six regulatory sites in mammalian cells. The regulation of FOXO3 by AMPK may play a crucial role in fine tuning gene expression programs that control energy balance and stress resistance in cells throughout life.