A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span
A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span
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DOI：
10.1016/j.cell.2006.03.046
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发表时间：
2006-06-02
期刊：
影响因子：
64.5
通讯作者：
Bonni, Azad
中科院分区：
文献类型：
--
作者：
Lehtinen, Maria K.;Yuan, Zengqiang;Bonni, Azad
氧化应激影响细胞的存活和稳态，但氧化应激的生物学效应的机制仍有待阐明。在这里，我们证明了蛋白激酶MST 1介导的氧化应激诱导的细胞死亡，在原代哺乳动物神经元直接激活FOXO转录因子。MST 1在叉头结构域内的保守位点磷酸化FOXO蛋白，这破坏了它们与14-3-3蛋白的相互作用，促进FOXO核转位，从而诱导神经元中的细胞死亡。我们还将MST-FOXO信号联系扩展到线虫。C的击倒。线虫MST 1直系同源物CST-1缩短寿命并加速组织衰老，而cst-1的过表达促进寿命并延缓衰老。cst-1诱导的寿命延长以daf-16依赖的方式发生。FOXO转录因子作为MST 1的主要和进化上保守的靶点的鉴定表明，MST激酶在包括细胞对氧化应激和寿命的响应在内的多种生物过程中发挥重要作用。
Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link to nematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissue aging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-span extension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity.