The function of mRNA export factor Gle1 in translation regulation

描述（由申请人提供）：信使rna （mrna）的核输出和mrna转化为蛋白质是两个最基本的细胞过程。这些过程，特别是翻译，在癌症进展中受到病毒的操纵和错误的调节，这使得对其机制的详细了解在设计治疗方法时非常宝贵。本提案旨在通过审查Gle1在翻译监管中的作用来阐明出口与翻译之间的联系。Gle1是真核生物从酵母向人类输出mRNA所必需的蛋白质。然而，初步证据表明Gle1在翻译过程中具有调控作用。目的1的目标是通过定向遗传筛选，细胞生物学和主要在酿酒酵母中的生化技术明确地建立这种作用。在第二部分中，我们将进一步阐明Gle1在翻译中的作用机制。这将通过首先检查其他已知的相互作用因素是否影响其在翻译中的作用以及确定受影响的翻译步骤来完成。这将需要一系列不同的技术，包括在酵母和哺乳动物细胞中进行的生化纯化和各种报告基因测定。Aim III将通过确定其他可能调节Gle1翻译的因素，如己基磷酸肌醇（IP6），试图进一步扩大这一研究，已知IP6调节Gle1的出口。长期目标是证明mRNA输出和翻译的关键活动的相互联系。

DESCRIPTION (provided by applicant): Nuclear export of messenger RNAs (mRNAs) and translation of mRNAs into protein are two of the most fundamental cellular processes. These processes, particularly translation, are manipulated by viruses and misregulated in cancer progression, which makes detailed knowledge of their mechanisms invaluable in designing therapeutics. This proposal is designed to elucidate links between export and translation by examining the role of Gle1 in translation regulation. Gle1 is an essential protein required for mRNA export in eukaryotes from yeast to humans. However, preliminary evidence indicates that Gle1 has a role in regulation of translation. The goal of aim I is to establish this role definitively through directed genetic screens, cell biology, and biochemical techniques primarily in the yeast S. cerevisiae. In aim II the mechanism by which Gle1 is acting in translation will be further elucidated. This will be accomplished by first examining whether other known interactors impact its role in translation and by also determining the step of translation affected. This will require a range of different techniques, including biochemical purification and various reporter assays, done in yeast and mammalian cells. Aim III will attempt to further broaden this research by identifying other factors that may regulate Gle1 in translation such as inositol hexakisphosphate (IP6), which is known to regulate Gle1 in export. The long-term goal is to demonstrate the interconnectedness of the critical activities of mRNA export and translation. Relevance: We propose to study links between two fundamental cellular activities. Viruses are known to hijack or manipulate these activities during infection, and these activities are also frequently not properly regulated in cancer progression. Therefore studying the mechanisms of these cellular processes may aid in designing future treatments as well as broadening our general understanding of cell biology.