Activation of the lifespan regulator p66Shc through reversible disulfide bond formation
Activation of the lifespan regulator p66Shc through reversible disulfide bond formation
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DOI：
10.1073/pnas.0800691105
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发表时间：
2008-04-15
影响因子：
11.1
通讯作者：
Steegborn, Clemens
中科院分区：
文献类型：
--
作者：
Gertz, Melanie;Fischer, Frank;Steegborn, Clemens
细胞命运和生物体寿命由一个复杂的信号网络控制，其功能障碍可导致各种与衰老相关的疾病。针对这些失败的重要保护是细胞凋亡，其可以由p66（Shc）响应于细胞应激而诱导。p66（Shc）作用和调节的精确机制以及p66（Shc）特异性N末端的功能仍有待确定。在这里，我们表明，p66（Shc）N末端形成一个负责细胞凋亡启动的氧化还原模块，并且该模块可以通过形成两个二硫键通过可逆的四聚体被激活。谷胱甘肽和硫氧还蛋白可以减少和抑制p66（Shc），导致基于巯基的氧化还原传感器系统，一旦细胞保护系统不能再科普细胞应激，该系统就启动细胞凋亡。
Cell fate and organismal lifespan are controlled by a complex signaling network whose dysfunction can cause a variety of aging-related diseases. An important protection against these failures is cellular apoptosis, which can be induced by p66(Shc) in response to cellular stress. The precise mechanisms of p66(Shc) action and regulation and the function of the p66(Shc)-Specific N terminus remain to be identified. Here, we show that the p66(Shc) N terminus forms a redox module responsible for apoptosis initiation, and that this module can be activated through reversible tetramerization by forming two disulfide bonds. Glutathione and thioredoxins can reduce and inactivate p66(Shc), resulting in a thiol-based re ox sensor system that initiates apoptosis once cellular protection systems cannot cope anymore with cellular stress.