Export and Maturation of Ribosomal Subunits

描述（由申请人提供）：核糖体负责蛋白质合成，是所有细胞所必需的。它对遗传密码的忠实翻译和对其活动的适当调节是正常细胞生长和发育所必需的。核糖体组装是一个复杂的动态过程，必须存在确保核糖体正确组装的机制，以保持翻译的保真度。此外，核糖体的生物发生占快速分裂细胞能量消耗的很大一部分，必须与细胞的代谢需要协调。事实上，许多癌症细胞的快速生长需要上调核糖体的生物发生。因此，了解调节核糖体生物发生的机制将为开发控制疾病状态下细胞增殖的新工具提供见解。对核糖体生物发生等基本细胞途径的描述也是智能开发新药所必需的，这些新药对其预期的细胞靶标具有特异性，而不会对其他细胞途径产生不利影响。这一建议旨在了解酵母中的大核糖体亚基如何从其在细胞核中的组装位点运输到其在细胞质中的功能位点并被激活以进行翻译。虽然我们使用酵母作为模式生物，但这些途径是高度保守的，我们的研究结果也将有助于理解人类细胞中的这些途径。本课题将：1)确定核糖体蛋白Rpl25和输出受体Arx1在大（60S）核糖体亚基的核输出中是如何合作的。2)建立所有已知的60S亚基细胞质成熟事件的有序通路。在这项工作中，我们将研究组装核糖体柄在核糖体的最后成熟步骤中所起的作用。3)确定是否核糖体生物发生与翻译相结合控制了60S亚基的最终成熟步骤。

DESCRIPTION (provided by applicant): The ribosome is responsible for protein synthesis and is essential in all cells. Its faithful translation of the genetic code and the proper regulation of its activity are necessary for normal cell growth and development. Ribosome assembly is a complex, dynamic process and mechanisms must exist that ensure the correct assembly of ribosomes in order to maintain the fidelity of translation. In addition, ribosome biogenesis accounts for a large portion of the energy expenditure of a rapidly dividing cell and must be coordinated with the metabolic needs of a cell. Indeed, the rapid cell growth of many cancers requires up-regulation of ribosome biogenesis. Thus, understanding the mechanisms regulating ribosome biogenesis will provide insight for the development of new tools for controlling cell proliferation in disease states. The delineation of fundamental cellular pathways such as ribosome biogenesis is also necessary for the intelligent development of new drugs that are specific to their intended cellular targets without impinging adversely on other cellular pathways. This proposal is directed at understanding how the large ribosomal subunit in yeast is transported from its site of assembly in the nucleus to its site of function in the cytoplasm and activated for translation. Although we use yeast as a model organism, these pathways are highly conserved and findings from our work will be relevant to understanding these pathways in human cells as well. This proposal will: 1) Identify how the ribosomal protein Rpl25 and the export receptor Arx1 collaborate in nuclear export of the large (60S) ribosomal subunit. 2) Develop an ordered pathway of all the known cytoplasmic maturation events of the 60S subunit. In this work we will examine the role that assembling the ribosome stalk plays in the final maturation steps of the ribosome. 3) Determine if ribosome biogenesis is coupled with translation in controlling the final maturation step of the 60S subunit. PUBLIC HEALTH RELEVANCE: This project delineates essential and fundamental molecular pathways that are conserved throughout eukaryotes. Understanding these pathways and how they are integrated with other cellular pathways will provide the intellectual underpinning for investigators carrying out translational research.