STRUCTURE AND FUNCTION OF THE COP9 SIGNALOSOME

描述（改编自申请人摘要）：调节基因的能力 对细胞外信号应答的表达模式对于 所有生物的生存和发展。上的知识 这种调控过程的分子机制是必要的， 了解包括人类疾病在内的许多复杂的生物现象。的 一种被称为COP 9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的表达和发育 植物的反应。已经表明，COP 9信号体是 在植物和动物之间结构上保守，然而， 细胞功能和这种复合物在动物发育过程中的作用是 未知 研究者对哺乳动物中单个亚基的初步研究 细胞暗示了COP 9信号体的潜在联系， 泛素-蛋白酶体介导的蛋白水解和细胞信号传导途径。使用 亚基1（COPS 1/GPS 1/FUS 6）作为模型，Wei博士进一步表明， 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，首席研究员的结果 表明S1/GPS 1亚基具有一个内在的阻遏物结构域， 可与复杂装配所需的结构域分离。此外，委员会认为， S1可以抑制信号传导激活，并介导基因表达的阻遏 通过不同的机制。为了激活理解的总体目标， COP 9信号体的结构和功能，主要研究者 目的：（1）探讨S1/GPS 1介导的抑制作用在细胞内的作用机制。 哺乳动物细胞;（2）研究S1的生理功能 通过遗传学方法研究拟南芥中的阻遏结构域;（3）研究拟南芥阻遏结构域的表达， COP 9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， COP 9信号体亚单位在信号刺激的泛素化中的作用 和哺乳动物细胞中代表性分子的降解;和（4） 通过基因打靶建立小鼠COP 9信号体动物模型， 揭示其发展作用。

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.