STRUCTURE AND FUNCTION OF THE COP9 SIGNALOSOME

COP9 信号体的结构和功能

• 批准号: 6603885
• 负责人: NING WEI
• 金额: $ 23.91万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603885
• 关键词: Arabidopsis; biological signal transduction; cell component structure /function; gene expression; gene targeting; laboratory mouse; molecular assembly /self assembly; mutant; protein protein interaction; protein structure function; ubiquitin

DESCRIPTION (adapted from applicant's abstract): The ability to regulate gene expression pattern in respond to extracellular signals is essential for the development and survival of all living organisms. The knowledge on the molecular mechanisms underlying such regulatory processes is necessary for understanding many complex biological phenomena including human diseases. The multi-component protein complex known as the COP9 signalosome was originally found to suppress the light activated gene expression and developmental responses in plants. It has been shown that the COP9 signalosome is structurally conserved between plants and animals, however the specific cellular functions and the role of this complex during animal development are unknown. The investigator's preliminary studies on individual subunits in mammalian cells have implied potential links of the COP9 signalosome to ubiquitin-proteasome mediated proteolysis and to cell signaling pathways. Using the subunit 1 (COPS1/GPS1/FUS6) as a model, Dr. Wei has further shown that this subunit confers a functional enhancing activity to repress light responses in Arabidopsis plant. In mammalian cells, the principal investigator's results showed that the S1/GPS1 subunit possess an intrinsic repressor domain that is separable from its structural domain required for complex assembly. Moreover, S1 can suppress signaling activation and mediate repression of gene expression by different mechanisms. To activate the overall goal of understanding the structure and function of COP9 signalosome, the principal investigator proposes: (1) to dissect the mechanisms of S1/GPS1 mediated repression in mammalian cells; (2) to investigate the physiological functions of the S1 repression domain in Arabidopsis by genetic approach; (3) to investigate the role of COP9 signalosome in the ubiquitin-proteasome pathway by examining the specific interaction with the machinery of the ubiquitin-proteasome pathway and the roles of the COP9 signalosome subunits in signal stimulated ubiquitination and degradation of representative molecules in mammalian cells; and (4) to establish an animal model of COP9 signalosome by gene targeting in mouse and to reveal its developmental role.

描述（改编自申请人的摘要）：调节基因的能力 响应细胞外信号的表达模式对于 所有生物体的发育和生存。有关的知识 这种调节过程背后的分子机制对于 了解许多复杂的生物现象，包括人类疾病。这 被称为 COP9 信号体的多组分蛋白质复合物最初是 发现抑制光激活基因表达和发育 植物中的反应。研究表明 COP9 信号体 植物和动物之间结构保守，但具体 细胞功能以及该复合物在动物发育过程中的作用 未知。 研究者对哺乳动物个体亚基的初步研究 细胞暗示 COP9 信号体与 泛素蛋白酶体介导的蛋白水解和细胞信号传导途径。使用 以子单元1（COPS1/GPS1/FUS6）为模型，魏博士进一步表明，这 亚基赋予功能增强活性以抑制光反应 拟南芥植物。在哺乳动物细胞中，主要研究者的结果 表明 S1/GPS1 亚基具有内在的抑制域 可与复杂组装所需的结构域分离。而且， S1 可以抑制信号传导激活并介导基因表达抑制 通过不同的机制。激活理解的总体目标 COP9信号体的结构与功能，主要研究者 提出：（1）剖析 S1/GPS1 介导的抑制机制 哺乳动物细胞； (2)考察S1的生理功能 通过遗传方法在拟南芥中抑制结构域； (3) 调查 通过检查 COP9 信号体在泛素-蛋白酶体途径中的作用 与泛素-蛋白酶体途径机制的特异性相互作用 COP9信号体亚基在信号刺激泛素化中的作用 以及哺乳动物细胞中代表性分子的降解； (4) 至 通过基因打靶建立小鼠COP9信号体动物模型 揭示其发展作用。