Protein kinase C β and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc
Protein kinase C β and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc
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DOI：
10.1126/science.1135380
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发表时间：
2007-02-02
期刊：
影响因子：
56.9
通讯作者：
Rizzuto, Rosario
中科院分区：
文献类型：
--
作者：
Pinton, Paolo;Rimessi, Alessandro;Rizzuto, Rosario
生长因子适配器Shc(p66(Shc))的66kodalton异构体通过在线粒体内产生活性氧种(ROS)将氧化损伤转化为细胞死亡。然而，p66(Shc)的线粒体促凋亡活性与细胞应激之间的信号联系尚不清楚。我们证明，在细胞内被氧化条件激活的蛋白激酶Cβ，在被Prolyl异构酶Pin1识别后，诱导p66Shc的磷酸化，并触发蛋白质的线粒体积累。一旦导入，p66(Shc)会引起线粒体钙反应和三维结构的改变，从而诱导细胞凋亡。这些数据确定了一条信号通路，激活了一种凋亡诱导剂，缩短了寿命，并可能成为抑制衰老的药物方法的潜在靶点。
The 66-kilodalton isoform of the growth factor adapter Shc (p66(Shc)) translates oxidative damage into cell death by acting as reactive oxygen species (ROS) producer within mitochondria. However, the signaling link between cellular stress and mitochondrial proapoptotic activity of p66(Shc) was not known. We demonstrate that protein kinase C beta, activated by oxidative conditions in the cell, induces phosphorylation of p66Shc and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase Pin1. Once imported, p66(Shc) causes alterations of mitochondrial Ca2+ responses and three-dimensional structure, thus inducing apoptosis. These data identify a signaling route that activates an apoptotic inducer shortening the life span and could be a potential target of pharmacological approaches to inhibit aging.