The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Protei

核仁拘留中心：囚禁蛋白质的长非编码 RNA 中心

基本信息

批准号：
8936277
负责人：
Stephen Lee
金额：
$ 30.32万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-24 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8936277
关键词：
Acclimatization Acidosis Amino Acids Antineoplastic Agents Applications Grants Biochemical Bioinformatics Biological Cell Culture Techniques Cell Nucleolus Cells Cellular Stress Response Cellular biology Code Communities Complex Critical Pathways Cues DNA biosynthesis Data Development Environment Eukaryotic Cell Exposure to Genetic Transcription Heat-Shock Response High temperature of physical object Human Genome Hyperthermia Hypoxia Immobilization Life Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolism Molecular Myocardial Infarction Nature Normal Cell Organism Oxygen Paper Pathway interactions Peptides Physiological Play Police Prisons Process Proteins Proteomics Proteus Publishing RNA Radiation Recombinant DNA Reporting Research Resistance Resistance Process Ribosomal RNA Ribosomes Role Scientist Stable Isotope Labeling Stimulus Stress Stroke Testing Toxin Translations Untranslated RNA Work base cancer therapy detention center environmental stressor extracellular extreme temperature fascinate innovation interest neoplastic cell nervous system disorder novel programs protein degradation public health relevance response stressor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Proteins During Stress (Note: papers from our group are cited) PROJECT SUMMARY The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various pathophysiological settings, including development, cancer and neurological disorders. We recently reported the unexpected discovery of stress-induced long noncoding RNAs derived from stimuli-specific loci of the ribosomal intergenic spacer (Mol. Cell (2012) 45:147), an enigmatic region of the human genome assumed to be transcriptionally inactive. Induction of intergenic spacer RNA (IGSRNA) converts the nucleolus from a factory of ribosomes to the nucleolar detention center: a molecular prison that detains specific proteins in response to extracellular stressors (Nature Cell Biol. (2004) 6:642; J.Cell. Biol. (2005) 170:733; Mol. Biol. Cell. (2013) 24: 2943). IGSRNAs capture and immobilize proteins in the nucleolar detention center by interacting with the Nucleolar Detention Sequence (NoDS), a discrete peptide code that regulates protein mobility (Mol. Biol. Cell (2007) 19:3966). We will show preliminary data that the rDNA intergenic spacer produces an array of novel and complex IGSRNAs that confine within the nucleolus distinct groups of proteins, depending upon environment cues. This enables cells to tailor their biological response to various adverse conditions by temporarily arresting critical pathways including DNA replication, transcription, translation and protein degradation. Based on these aforementioned rationales, we propose the following hypothesis: IGSRNAs induce cellular acclimatization to environmental stressors by capturing and immobilizing distinct proteins in the nucleolar detention center. In the Specific Aims, we will: 1- decipher the ribosomal intergenic spacer as a hub of lncRNAs responsive to environmental cues; 2- uncover the stimuli-specific nucleolar detention centers; 3- explore the biological and biochemical consequences of stress-specific IGSRNA-induced nucleolar detention. The discovery of the IGSRNA-regulated nucleolar detention pathway opens a unique and remarkable window of opportunity to investigate a largely unexplored post-translational mechanism involved in the cellular stress response. Study of the IGSRNA-directed pathway will yield significant conceptual advances in our understanding of critical adaptive/resistance processes to stressors encounter by cells, such as the acidotic tumor microenvironment, hyperthermia, and exposure to anti-cancer drugs.

描述（由申请人提供）：核仁拘留中心：在应激期间囚禁蛋白质的长非编码 RNA 中心（注：引用了我们小组的论文）项目摘要细胞适应各种应激条件的能力起着决定性作用。我们最近意外地发现了源自核糖体刺激特异性位点的应激诱导的长非编码 RNA。基因间间隔区（Mol. Cell (2012) 45:147），人类基因组中的一个神秘区域，被认为是转录失活的。基因间间隔区 RNA (IGSRNA) 的诱导将核仁从核糖体工厂转变为核仁滞留中心：a分子监狱，扣留响应细胞外应激源的特定蛋白质（Nature Cell Biol. (2004) 6:642； J.Cell. (2005) 170:733；IGSRNA 通过与核仁滞留序列 (NoDS) 相互作用来捕获和固定蛋白质。调节蛋白质迁移率的肽代码（Mol.Biol.Cell（2007）19：3966）。初步数据表明，rDNA 基因间间隔区产生一系列新颖且复杂的 IGSRNA，这些 IGSRNA 根据环境线索将不同的蛋白质组限制在核仁内，这使得细胞能够通过暂时阻止包括 DNA 在内的关键途径来调整其对各种不利条件的生物反应。基于这些提到的原理，我们提出以下假设：IGSRNA 通过捕获和固定核仁滞留中心中的不同蛋白质来诱导细胞对环境应激源的适应。具体目标，我们将： 1- 破译核糖体基因间间隔区作为对环境线索作出反应的 lncRNA 的枢纽； 2- 揭示刺激特异性的核仁滞留中心； 3- 探索应激特异性 IGSRNA 诱导的生物学和生化后果。 IGSRNA 调控的核仁滞留途径的发现为研究涉及核仁滞留的很大程度上未经探索的翻译后机制打开了一个独特而显着的机会之窗。 IGSRNA 介导的通路的研究将在我们理解细胞遇到的应激源（例如酸中毒的肿瘤微环境、高温和抗癌药物暴露）的关键适应性/抵抗过程方面产生重大的概念性进展。