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

• 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
• 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

 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（由适用提供）：核仁拘留中心：在压力期间监禁蛋白质的长期非编码RNA的枢纽（请注意：我们组的论文被引用）项目摘要摘要细胞适应多种应激状况的能力在各种病理生理学设置中起着至关重要的作用，包括发育，癌症和神经学疾病。我们最近报道了意外发现核糖体间间隔物的刺激特异性位置的应力诱导的长期非编码RNA（Mol。Cell（2012）45：147），这是人类基因组的神秘区域，被认为是转录性不活跃的。 Induction of intergenic spacer RNA (IGSRNA) converts the nuclear olus from a factory of ribosomes to the nuclear detention center: a molecular prison that defines 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). IGSRNA通过与核仁拘留序列（NODS）相互作用，将蛋白质捕获并固定在核拘留中心中，这是一种调节蛋白质迁移率的离散肽代码（Mol。Biol。Cell。Cell（2007）19：3966）。我们将表明初步数据表明，rDNA间间隔物会产生一系列新颖而复杂的IGSRNA，这些IGSRNA局限于核不同的蛋白质群中，具体取决于环境提示。这使细胞能够通过临时阻止包括DNA复制，转录，翻译和蛋白质降解的关键途径来定制其对各种不良条件的生物学反应。基于这些优先级的理由，我们提出了以下假设：IGSRNA通过捕获和固定在核拘留中心中的不同蛋白质来诱导细胞适应环境压力源。在具体目的中，我们将：1-解读核糖体间间隔物，作为对环境线索有效的LNCRNA的枢纽； 2-揭开刺激特异性核拘留中心； 3-探索应力特异性IGSRNA诱导的核拘留的生物学和生化后果。 IGSRNA调节的核拘留途径的发现为研究细胞应激反应涉及的主要意外翻译后机制开辟了一个独特而出色的机会窗口。对IGSRNA定向途径的研究将在我们对临界适应性/抗药性过程的理解中对遇到的压力源（例如酸性肿瘤微环境，高温和暴露于抗癌药物）遇到的压力。