日前,美国托马斯杰弗逊大学生物化学和分子生物系研究人员发现一种叫做“C. elegans”微小蛔虫体内单一蛋白质水平可以确定它们寿命的长短。天生不具备这种抑制蛋白(arrestin)的蛔虫寿命比正常蛔虫长三分之一,而那些抑制蛋白数量是正常3倍的蛔虫则寿命短三分之一。
研究人员指出,抑制蛋白与其它几种蛋白质发生交互作用,从而调控寿命长短。人体相对应的抑制蛋白是PTEN,它也是一种肿瘤抑制体。目前,这项最新研究报告发表在《生物化学》杂志上。
生物化学和分子生物系教授杰弗里-本诺维克(Jeffrey L. Benovic)博士称,由于虫类许多蛋白质与人类相匹配,这项发现对于人体生物学和理解癌症的发展具有特殊贡献。尽管人体生物学更加复杂,但这种基因对于人类和虫类之间的关联性暗示着相同的交互作用也存在于哺乳动物。我们需要更深入地展开研究,从而获得更多的重大发现。
研究人员使用蛔虫作为实验模型,由于蛔虫提供一种简单的系统便于研究与人体生物学相关的基因和蛋白质,例如:“C. elegans”蛔虫拥有一个抑制蛋白基因,相对应地人类就有4个。蠕虫拥有302个神经细胞,就相当于人体大脑1000亿个脑细胞。此外,这种蛔虫两至三周的生命周期对于观测长寿效应更加直观有效。
本诺维克和这项研究报告第一作者博士后生艾梅-帕尔米特萨(Aimee Palmitessa)研究了由G蛋白质对受体激活的信息路径,这些蛋白质对受体可与所有类型的激素、敏感刺激物(比如:光线、气味等)、神经传递素等结合在一起,它们将刺激细胞内的梯状信号,并控制许多生理进程,这种机理可用于研制药物。
本诺维克说:“当蛔虫具备这些蛋白质对受体,它们实际上就变得更加复杂,人类大概有800种不同的G蛋白质对受体,而蛔虫依据不同的感觉刺激(不同的神经传递素和激素)具有大约1800种G蛋白质对受体。”
最初,抑制蛋白被发现于细胞激活状态下的蛋白质对受体,本诺维克说:“这种蛔虫提供了一种非常好的方法用于研究单个抑制蛋白如何与蛋白质受体发生交互感应。”
在这项研究中,帕尔米特萨删除了蛔虫体内的单个抑制蛋白基因,观测会发生什么状况,令她惊奇的是,这些蛔虫的寿命显著延长。她同时发现体内携带更多抑制蛋白基因的蛔虫寿命会较短。
本诺维克博士称,人类抑制蛋白基因和PTEN之间的关联性并不清楚,我们并不知道是否人类抑制蛋白基因可以控制PTEN的功能,或者在癌症发育阶段是否出现任何抑制蛋白基因水平的变化。未来更深入的研究有助于我们研制抑制人体癌症的有效医学措施。
原文出处:
JBC doi: 10.1074/jbc.M110.104612
Arrestin and the Multi-PDZ Domain-containing Protein MPZ-1 Interact with Phosphatase and Tensin Homolog (PTEN) and Regulate Caenorhabditis elegans Longevity
Aimee Palmitessa and Jeffrey L. Benovic1
Arrestins are multifunctional adaptor proteins best known for their role in regulating G protein-coupled receptor signaling. Arrestins also regulate other types of receptors, including the insulin-like growth factor receptor (IGF-1R), although the mechanism by which this occurs is not well understood. In Caenorhabditis elegans, the IGF-1R ortholog DAF-2 regulates dauer formation, stress resistance, metabolism, and lifespan through a conserved signaling cascade. To further elucidate the role of arrestin in IGF-1R signaling, we employed an in vivo approach to investigate the role of ARR-1, the sole arrestin ortholog in C. elegans, on longevity. Here, we report that ARR-1 functions to positively regulate DAF-2 signaling in C. elegans. arr-1 mutant animals exhibit increased longevity and enhanced nuclear localization of DAF-16, an indication of decreased DAF-2 signaling, whereas animals overexpressing ARR-1 have decreased longevity. Genetic and biochemical analysis reveal that ARR-1 functions to regulate DAF-2 signaling via direct interaction with MPZ-1, a multi-PDZ domain-containing protein, via a C-terminal PDZ binding domain in ARR-1. Interestingly, ARR-1 and MPZ-1 are found in a complex with the phosphatase and tensin homolog (PTEN) ortholog DAF-18, which normally serves as a suppressor of DAF-2 signaling, suggesting that these three proteins work together to regulate DAF-2 signaling. Our results suggest that the ARR-1-MPZ-1-DAF-18 complex functions to regulate DAF-2 signaling in vivo and provide insight into a novel mechanism by which arrestin is able to regulate IGF-1R signaling and longevity.