SUMO conjugation in cell biology and Development

细胞生物学和发育中的相扑结合

• 批准号: 7196827
• 负责人: ALBERT J COUREY
• 金额: $ 24.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196827
• 关键词: Affinity; Animal Model; Biochemical; Biochemical Genetics; Biogenesis; Biological; Biological Phenomena; Biological Process; Cell Nucleus; Cells; Cellular biology; Chromatin Structure; Complex; Databases; Development; Disease model; Drosophila genus; Drosophila melanogaster; Embryo; Embryonic Development; Embryonic Pattern Specification; Enzymes; Epigenetic Process; Genes; Genetic; Genotype; Goals; Homeobox Genes; Huntington Disease; Inheritance Patterns; JUN gene; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Oncogene Proteins; Organism; Pathway interactions; Pattern Formation; Play; Polycomb; Post-Translational Protein Processing; Process; Protein p53; Proteins; Proteomics; Regulation; Repression; Research; Role; SAM Domain; Specificity; Staging; Structure; Sumoylation Pathway; System; Techniques; Testing; Transcriptional Regulation; Transgenes; Tumor Suppressor Proteins; Ubiquitin Like Proteins; Wing; biological adaptation to stress; fitness; fly; genetic regulatory protein; human Huntingtin protein; human disease; protein folding; research study

DESCRIPTION (provided by applicant): Project Summary: SUMO is a ubiquitin-like protein that is reversibly conjugated to a wide variety of target proteins, thereby serving as a flexible switch to control protein subcellular localization and biochemical activity. SUMO conjugation ("sumoylation") plays central roles in many crucial biological processes including epigenetic inheritance and pattern formation. The long-term goal of this research is to illuminate the connections between sumoylation and these biological phenomena using the easily manipulated model organism Drosophila melanogaster. The specific aims are: 1. To determine the role of SUMO in Polycomb Group (PcG) function. PcG factors play essential roles in maintaining the silent epigenetic state of genes that regulate development. Two PcG factors, Ph and Scm, appear to be regulatory targets of sumoylation. Genetic, cell biological, and biochemical approaches will be employed to make mechanistic connections between the sumoylation of these proteins and transcriptional silencing. 2. To carry out a system wide analysis of the effects of genotype and developmental stage on the spectrum of SUMO-conjugated proteins. The pleiotropic roles of SUMO suggest the existence of many unidentified SUMO conjugation targets. Proteomic techniques will be used to characterize the spectrum of SUMO conjugated proteins in the intact organism as a function of genotype and developmental stage. The creation of a multi-dimensional database of SUMO-conjugated proteins will allow us to test hypotheses about how SUMO conjugating and deconjugating enzymes determine the specificity of conjugation, and about the role of SUMO in such processes as protein biogenesis, epigenetic transcriptional control, and embryogenesis. Relevance: The sumoylation pathway has been implicated in both neurodegenerative disorders and cancer. For example, sumoylation of Huntingtin, the pathogenic protein in Huntington's disease, exacerbates neurodegeneration in a Drosophila model of this disease. Furthermore, the sumoylation of numerous oncoproteins (c-jun, elk-1, and TEL) and tumor suppressor proteins (p53, RB, and PML) modulates their function. Consequently, the research proposed here will advance our understanding of human disease.

描述（由申请人提供）：项目摘要：Sumo是一种类似泛素的蛋白质，可逆地将其与多种靶蛋白结合在一起，从而作为控制蛋白质亚细胞定位和生化活性的灵活开关。 Sumo共轭（“ Sumoylation”）在许多关键的生物学过程中扮演着核心作用，包括表观遗传遗传和模式形成。这项研究的长期目标是使用易于操纵的模型有机体果蝇Melanogaster来阐明Sumoylation与这些生物学现象之间的联系。具体目的是：1。确定SUMO在PolyComb组（PCG）函数中的作用。 PCG因素在维持调节发展的基因的沉默表观遗传状态方面起着重要作用。 pH和SCM的两个PCG因素似乎是Sumoylation的调节靶标。将采用遗传，细胞生物学和生化方法来建立这些蛋白质的Sumoylation与转录沉默之间的机械连接。 2。进行系统广泛的分析，对基因型和发育阶段对Sumo偶联蛋白的影响。 Sumo的多效性作用表明存在许多未鉴定的Sumo共轭靶标。蛋白质组学技术将用于表征完整生物体中的共和性共轭蛋白的光谱，这是基因型和发育阶段的函数。 Sumo偶联蛋白的多维数据库的创建将使我们能够测试Sumo共轭和解偶联酶如何确定共轭的特异性以及Sumo在此类过程中作为蛋白质生物发生，表观遗传转录控制和植入物的作用的假设。相关性：Sumoylation途径与神经退行性疾病和癌症有关。例如，亨廷顿病（Huntingtin）（亨廷顿氏病中的致病蛋白）的sumoylation加剧了这种疾病的果蝇模型中的神经变性。此外，许多癌蛋白（C-JUN，ELK-1和TEL）以及肿瘤抑制蛋白（P53，RB和PML）的sumoylation调节其功能。因此，这里提出的研究将提高我们对人类疾病的理解。