STRUCTURE AND FUNCTION OF THE COP9 SIGNALOSOME

COP9 信号体的结构和功能

• 批准号: 6387233
• 负责人: NING WEI
• 金额: $ 23.51万
• 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/6387233
• 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(摘自申请者的摘要)：调控基因的能力 响应细胞外信号的表达模式对于细胞外信号是必不可少的 所有生命有机体的发展和生存。关于这方面的知识 这种调控过程背后的分子机制是必要的 了解许多复杂的生物现象，包括人类疾病。这个 被称为COP9信号体的多组分蛋白质复合体最初是 发现抑制光激活基因的表达和发育 植物的反应。已有研究表明，COP9信号体是 在植物和动物之间在结构上保守，然而特定的 这种复合体在动物发育过程中的细胞功能和作用是 未知。 研究人员对哺乳动物个体亚基的初步研究 细胞中含有COP9信号小体潜在的连接 泛素-蛋白酶体介导的蛋白分解和细胞信号通路。vbl.使用 亚基1(COPS1/GPS1/FUS6)作为模型，魏博士进一步证明了这一点 亚基赋予功能增强活性，以抑制光反应 拟南芥属植物。在哺乳动物细胞中，首席研究人员的结果 表明S1/GPS1亚单位具有一个固有的抑制器域，即 可与复杂组装所需的结构域分离。此外， S1可以抑制信号的激活和介导基因表达的抑制 通过不同的机制。要激活理解 首席研究者COP9信号小体的结构和功能 建议：(1)剖析S1/GPS1介导的抑制作用的机制。 哺乳动物细胞；(2)研究S1的生理功能 利用遗传学方法研究拟南芥中的阻遏结构域 通过检测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和 COP9信号小体亚基在信号刺激泛素化中的作用 和哺乳动物细胞中代表性分子的降解；以及(4) 用基因打靶技术建立小鼠COP9信号体动物模型 揭示其发展作用。