Shc相关磷酸化酪氨酸适配蛋白在衰老过程中的调控作用

Regulatory effects of Shc-related phosphotyrosine adaptor proteins on aging

衰老相关的氧化应激理论和自由基理论能部分地解释衰老过程而被越来越广泛地接受。p66Shc(66-kilodalton isoform of Shcgene products)基因编码是一种磷酸化酪氨酸信号适配蛋白,敲除p66Shc基因的小鼠模型寿命可延长30%,并表现出对氧化应激的抗性。氧化应激时,p66Shc的Ser36位点被磷酸化,进而致叉头转录因子(forkhead-type transcription factors,FKHR)失活,而FKHR可调节胞内抗氧化基因的表达。p66Shc信号转导与进化上保守的寿命相关信号转导有直接联系。Shc(Src homologue and collagen protein)基本不表达于成人脑和脊髓的成熟神经元中。然而,在神经系统中存在两种Shc同源基因,Sck/ShcB和N-Shc/ShcC;并有证据表明它们在氧化应激和脑的衰老中发挥作用。Shc相关基因的表达在老化过程中受到影响,这可能与衰老时的细胞功能障碍、应激反应和/或认知功能退化有关。

Aging-related oxidative stress and free radical theory has become accepted increasingly as explaination, at least in part of the aging process. In murine models of aging, a genetic deficiency of the p66^Shc（66-kilodalton isoform of Shc gene products） gene, which encodes a phosphotyrosine signal adapter protein, extends life span by 30% , and confers resistance to oxidative stress. Upon oxidative stress,p66^Shc is phosphorylated at Ser36, contributing to inactivation of the forkhead-type transcription factors （FKHR/ FoxO1 ） , which regulates the gene expression of cellular antioxidants. The p66^Shc has a direct connection with the life span related signaling, which is conserved evolutionarily. Shc is basically not expressed in mature neurons of the adult brain and spinal cord. Instead, two Shc homologues, Sck/ShcB and N-Shc/ ShcC, which have been proved to be effective on oxidative stress and aging, are expressed in neural system. The expression of Shc-related genes is affected in the aging process, which may be relevant to cellular dysfunction, stress response and/or cognitive decline during aging.