Monitoring mechanisms in mammalian ribosome biogenesis

哺乳动物核糖体生物发生的监测机制

• 批准号: 7575779
• 负责人: DIMITRI G PESTOV
• 金额: $ 23.07万
• 依托单位: UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575779
• 关键词: Address; Anabolism; Binding; Biochemical; Biochemical Genetics; Biogenesis; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Proliferation; Cells; Complex; Defect; Dissection; Family member; GTP-Binding Proteins; Goals; Guanine Nucleotides; Guanosine Triphosphate Phosphohydrolases; Hydrolysis; In Vitro; Link; Malignant Neoplasms; Mammalian Cell; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Monitor; Mus; Mutation; Nucleolar Proteins; Pathway interactions; Play; Process; Property; Protein p53; Proteins; Refractory; Ribosomal RNA; Ribosomes; Role; Signal Transduction; Stress; System; TP53 gene; Therapeutic Intervention; cell growth; conformational conversion; design; human disease; in vivo; insight; mutant; novel; research study; response; sensor

DESCRIPTION (provided by applicant): Synthesis of new ribosomes is an essential cellular activity and it is becoming increasingly clear that ribosome biogenesis plays an important role in cancer and human disease. However, molecular mechanisms of this highly complex process and its links to other cellular pathways remain inadequately understood, especially in a mammalian system. Recent evidence indicates that mammalian cells possess a surveillance system that communicates perturbations in ribosome synthesis to the tumor suppressor p53. It is currently unknown how errors in ribosome assembly are recognized and which components in the ribosome biogenesis machinery mediate signaling to the p53 pathway. We seek to understand the mechanisms that provide monitoring of ribosome biogenesis in mammalian cells through analysis of the newly discovered nucleolar GTP-binding proteins (GTPases) Nog1 and Nug1A/B. Recent experimental evidence shows that the function of these GTPases is essential for synthesis of 60S ribosomal subunits and also implicates them as potential signaling links between ribosome synthesis and proliferation control pathways. The studies proposed here are designed to elucidate the role of the mammalian nucleolar GTPases in surveillance of ribosome biogenesis and to gain insight into the molecular mechanisms of their action. We will begin by addressing two questions to assess the monitoring function of the nucleolar GTPases. What is the role of mouse Nog1 and Nug1A/B in rRNA maturation? How does their function contribute to the accuracy of ribosome biogenesis and signaling to the p53 network? By using a combination of biochemical and genetic approaches, we will further investigate the molecular mechanisms of a model representative of the group, Nog1. What role do guanine nucleotide binding and hydrolysis play in the activities of this GTPase? What proteins serve as effectors and regulators of Nog1 function and how do they influence its GTPase cycle? Collectively, these studies should provide significant new information on a novel group of GTP-binding proteins, yield mechanistic insights into ribosome assembly and contribute to our understanding of the link between ribosome biogenesis and proliferation control in mammalian cells.

描述（由申请人提供）： 新核糖体的合成是一项重要的细胞活动，并且越来越清楚的是，核糖体生物发生在癌症和人类疾病中发挥着重要作用。然而，这一高度复杂过程的分子机制及其与其他细胞途径的联系仍然没有得到充分的了解，特别是在哺乳动物系统中。最近的证据表明，哺乳动物细胞拥有一个监视系统，可将核糖体合成的扰动传递给肿瘤抑制因子 p53。目前尚不清楚核糖体组装中的错误是如何被识别的，以及核糖体生物合成机制中的哪些成分介导 p53 途径的信号传导。我们试图通过分析新发现的核仁 GTP 结合蛋白 (GTPase) Nog1 和 Nug1A/B 来了解监测哺乳动物细胞中核糖体生物发生的机制。最近的实验证据表明，这些 GTP 酶的功能对于 60S 核糖体亚基的合成至关重要，并且还表明它们是核糖体合成和增殖控制途径之间的潜在信号传导联系。这里提出的研究旨在阐明哺乳动物核仁 GTP 酶在核糖体生物合成监测中的作用，并深入了解其作用的分子机制。我们将首先解决两个问题来评估核仁 GTP 酶的监测功能。小鼠 Nog1 和 Nug1A/B 在 rRNA 成熟中起什么作用？它们的功能如何有助于核糖体生物发生和 p53 网络信号传导的准确性？通过结合生化和遗传学方法，我们将进一步研究该群体的代表模型Nog1的分子机制。鸟嘌呤核苷酸结合和水解在该 GTP 酶的活性中起什么作用？哪些蛋白质充当 Nog1 功能的效应子和调节子？它们如何影响其 GTP 酶循环？总的来说，这些研究应该提供关于一组新型 GTP 结合蛋白的重要新信息，产生对核糖体组装的机制见解，并有助于我们理解哺乳动物细胞中核糖体生物发生和增殖控制之间的联系。