Translational control of gene expression and the choice between cell death and proliferation

蛋白质在细胞中承担着大部分的酶和结构功能。因此，在特定细胞中发现的蛋白质分子的种类决定了它的特征，细胞通过调整其集合中某些或许多蛋白质的丰度来对环境的变化做出反应。蛋白质组装的指令在基因中编码，这一信息通过称为信使(M)RNA的中间分子表达。基因转录成信使核糖核酸分子和随后由核糖体翻译成蛋白质都是基因表达途径中严格控制的步骤。错误的基因表达是人类疾病的一个主要因素，翻译失调与越来越多的疾病有关，如癌症和心血管疾病、病毒感染以及较少出现的遗传综合征。这里提出的项目是因为越来越多的证据表明，翻译调控在控制细胞死亡和存活之间的平衡中发挥了作用。打破这种平衡会给生物体带来灾难性的后果，因为它参与了许多重大疾病(如中风、心力衰竭、神经退化、艾滋病、癌症、自身免疫)。我们的目的是检验一种假设，即一个被称为p97-DAP5-Nat1的假定的翻译调节因子，以及一种通过内部核糖体进入启动翻译的专门机制对于维持这种平衡是重要的。为了研究这一点，我们将使用DNA芯片，这是基因组学研究的一种新工具，可以在一次实验中测量数千个mRNA分子的水平。可以想象，对这些特殊翻译机制的了解将为治疗干预带来新的靶点，这项工作将为未来探索这些途径提供一些实验工具。

Proteins carry out most enzymatic and structural functions in a cell. Thus, the kinds of protein molecules that are found in a given cell determine its characteristics and cells respond to changes in their environment by adjusting the abundance of some or many proteins in their collection. The instructions for the assembly of proteins are encoded in the genes and this information is expressed via intermediary molecules called messenger (m)RNA. Both, transcription of the genes into mRNA molecules and their subsequent translation by the ribosomes into protein are tightly controlled steps in the gene expression pathway. Erroneous gene expression is a major factor in human disease and dysregulation of translation is linked to a growing spectrum of illnesses such as cancer and cardiovascular disease, viral infection, and less frequent hereditary syndromes. The project proposed here is prompted by emerging evidence for a role of translational regulation in controlling the balance between cell death and survival. Tipping this balance has disastrous consequences for an organism as evidenced by its involvement in many major disorders (e. g. stroke, heart failure, neurodegeneration, AIDS, cancer, autoimmunity). Our aim is to test the hypothesis that a putative translational regulator termed p97-DAP5-NAT1, and a specialised mechanism of translation initiation by internal ribosome entry are important for the maintenance of this balance. To investigate this, we will employ DNA chips, a novel tool from Genomics research that allows the measurement of the levels of thousands of mRNA molecules in a single experiment. It is conceivable that knowledge of these special mechanisms of translation will lead to novel targets for therapeutic intervention, and this work will contribute some of the experimental tools to explore these avenues in the future.