Export and Maturation of Ribosomal Subunits

描述(申请人提供)：核糖体负责蛋白质合成，在所有细胞中都是必不可少的。它对遗传密码的忠实翻译和对其活动的适当调节对于正常的细胞生长和发育是必要的。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，才能保持翻译的保真度。此外，核糖体生物合成占快速分裂细胞能量消耗的很大一部分，必须与细胞的新陈代谢需求相协调。事实上，许多癌症的快速细胞生长需要上调核糖体的生物发生。因此，了解调控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洞察力。描绘核糖体生物发生等基本细胞途径对于智能开发针对其预期细胞靶点的新药也是必要的，而不会对其他细胞途径产生不利影响。这项建议旨在了解酵母中的大核糖体亚基是如何从其在细胞核中的组装位置运输到其在细胞质中的功能位置并被激活以进行翻译的。尽管我们使用酵母作为模式生物，但这些途径是高度保守的，我们的工作发现也将与理解人类细胞中的这些途径相关。这一建议将：1)确定核糖体蛋白Rpl25和输出受体Arx1如何在大的(60S)核糖体亚基的核输出中合作。2)建立了60S亚基所有已知的细胞质成熟事件的有序途径。在这项工作中，我们将研究组装核糖体茎在核糖体的最终成熟步骤中所起的作用。3)确定核糖体的生物发生与翻译是否耦合控制60S亚基的最终成熟步骤。 与公共健康相关：这个项目描绘了在真核生物中保守的基本和基本的分子途径。了解这些途径以及它们是如何与其他细胞途径整合的，将为开展翻译研究的研究人员提供智力基础。

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.