Role of translation elongation factor 1B (eEF1B) in regulating protein synthesis in response to oxidative stress in yeast

所有的有机体都必须对其外部环境的变化做出反应。随着基因组序列的获得，越来越多的注意力集中在分析这些适应性反应过程中基因表达/转录谱的变化。信使核糖核酸到蛋白质的翻译是基因表达途径的基本组成部分。然而，关于翻译控制机制在应激反应中的作用，人们知之甚少，这也是本研究的重点。这一应用是基于我们的初步发现，即氧化应激导致蛋白质合成的快速抑制。这种对蛋白质合成的全球抑制被广泛认为是生物系统对应激条件的反应。在应激条件下阻止蛋白质合成可能会让有机体有时间引导基因表达，以产生抵御应激或解毒所需的新分子。我们的数据显示，氧化应激在多个水平上抑制蛋白质的合成。这一综合性研究计划的目标是了解这些调控机制的分子细节。这项研究将集中在氧化应激，这是大多数生物系统的一个主要问题。活性氧和自由基是正常新陈代谢和暴露在包括阳光在内的环境因素下的有毒副产品。所有生物体，包括人类，都含有有效的抗氧化剂，如维生素A和C，以及可以解毒这些有害分子的酶，如过氧化氢酶和超氧化物歧化酶。然而，在极端条件下，活性氧会压倒抗氧化防御系统，导致所谓的“氧化应激”。了解细胞如何对氧化应激做出反应是很重要的，因为它与许多疾病有关，包括癌症、神经退行性疾病和心血管疾病。此外，细胞和组织的氧化损伤可能会导致老化细胞的生理功能下降。本研究将利用酿酒酵母作为模式生物。酵母为研究这些类型的过程提供了一个理想的模型系统，因为它在遗传上是易驯化的，并且已经成为大多数后基因组研究的首选有机体。酵母和人类细胞中的压力保护系统之间也有高度的保守性，使其成为本研究的理想有机体。

All organisms must respond to changes in their external environment. With the availability of genome sequences much attention has focused on analyzing the changes in gene expression/transcription profiles during these adaptive responses. The translation of mRNA into protein is a fundamental component of the gene expression pathway. However, relatively little is known regarding the role of translational control mechanisms in the response to stress conditions, which is the focus of this proposed study. This application is based on our preliminary findings showing that oxidative stress causes a rapid inhibition of protein synthesis. Such a global inhibition of protein synthesis is widely recognised as a response of biological systems to stress conditions. Preventing protein synthesis during stress conditions may allow time for organisms to direct gene expression towards the production of new molecules required to protect against or detoxify the stress. Our data show that oxidative stress inhibits protein synthesis at multiple levels. The goal of this comprehensive research programme is to understand the molecular details of these regulatory mechanisms. This study will focus on oxidative stress which is a major problem for most biological systems. Reactive oxygen species and free radicals are produced as toxic by-products of normal metabolism and through exposure to environmental factors including sunlight. All organisms, including humans, contain effective antioxidants such as vitamins A and C and enzymes, such as catalase and superoxide dismutase, that can detoxify these harmful molecules. However, under extreme conditions reactive oxygen species can overwhelm the antioxidant defences resulting in a so-called 'oxidative stress'. It is important to understand how cells respond to an oxidative stress because it is implicated in many diseases including cancer, neurodegenerative and cardiovascular diseases. In addition, oxidative damage to cells and tissues can contribute to the decline in physiological function that occurs in ageing cells. This research will make use of the yeast Saccharomyces cerevisiae as a model organism. Yeast offers an ideal model system to study these types of processes since it is genetically tractable and has served as the organism of choice for most post-genomic studies. There is also a high degree of conservation between the stress-protective systems in yeast and human cells making it an ideal organism for this study.