COOPERATION BETWEEN C-MYB AND THE EBV Z TRANSACTIVATOR

C-MYB 与 EBV Z 交易者之间的合作

• 批准号: 2106642
• 负责人: DAVID E GUTSCH
• 金额: $ 7.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2106642
• 关键词: Epstein Barr virus; cell differentiation; cell line; chimeric proteins; estrogen receptors; gene deletion mutation; gene induction /repression; hematopoiesis; intermolecular interaction; oncoproteins; protein structure function; protooncogene; site directed mutagenesis; transcription factor; virus protein; virus replication

This is an application for a K08 award for Dr. David Gutsch, designed to further develop his skills in molecular biology, and to provide experience is the field of oncology, specifically in the study of oncogenes. His prior training at the Lineberger Cancer Center at the University of North Carolina focused on gene regulation of Epstein-Barr virus (EBV) replication. EBV is a significant human pathogen, causing Burkitt's lymphoma, nasopharyngeal carcinoma, and lymphomas in immunocompromised hosts. Preliminary work by Dr. Gutsch and colleagues has identified an interaction between an important EBV immediate-early protein, Z, and the c-myb proto-oncogene. Both of these proteins, which function as transcriptional transactivators, synergistically enhance the ability of the other to transactivate target promoters. The Z protein, which resembles c-Fos and belongs to the bZIP family, is responsible for initiating viral productive infection. C-Myb is required for normal hematopoietic development and for normal cell cycle progression. This novel interaction could potentially enhance disruption of EBV latency by Z, and may serve as an example of a general interaction between bZIP proteins and members of the Myb family. The experiments in this proposal will extend these preliminary findings, establish the generality of the bZIP/Myb interaction, work out the mechanistic details of such an interaction, and explore its potential biologic relevance. First, the precise domains of the Z and c-Myb proteins that are responsible for synergistic cooperation will be mapped in detail. Second, multiple bZIP proteins and members of the Myb family of proteins will be tested for synergistic cooperation between one another. Third, it will be established whether Z and c-Myb can physically contact each other directly. Fourth, the role of the Z protein in disrupting c-Myb function as an inhibitor of cellular differentiation will be examined. Finally, the effect of c-Myb upon EBV replication will be analyzed. Additional educational activities planned for this K08 program include: graduate level coursework in virology, cellular function, and molecular function, and molecular biology; scientific seminars, including a weekly Cancer Center Grand Rounds scientific series; weekly lab meetings; journal clubs; and travel to attend meetings to present data and discuss results with other scientists. Through these learning tools and through the experimental work detailing the molecular basis for the cooperation between Z and c-Myb, this K08 award should provide a firm basis for Dr. Gutsch to begin a career as an independent medical researcher.

这是David Gutsch博士的K08奖的申请，旨在 进一步发展他在分子生物学方面的技能，并提供 经验是肿瘤学领域，特别是在研究 癌基因。 他先前在Lineberger癌症中心的培训 北卡罗来纳大学的重点是爱泼斯坦 - 巴尔的基因调节 病毒（EBV）复制。 EBV是一种重要的人类病原体，导致 伯基特的淋巴瘤，鼻咽癌和淋巴瘤 免疫功能低下的宿主。 Gutsch博士及其同事的初步工作 已经确定了重要的EBV立即进行的相互作用 蛋白质，Z和C-MYB原型癌基因。 这两种蛋白质都 作为转录反式激活器的功能，协同增强了 对方反式激活目标启动子的能力。 Z蛋白， 类似于C-Fos，属于BZIP家族，负责 引发病毒生产感染。 c-myb是正常的 造血发育和正常细胞周期进程。 这 新颖的相互作用可能会通过 z，可以作为BZIP一般相互作用的一个例子 蛋白质和MYB家族的成员。 该提案中的实验 将扩展这些初步发现，确定 BZIP/MYB互动，确定此类机械细节 相互作用，并探索其潜在的生物学相关性。 首先， 负责的Z和C-MYB蛋白的精确域 协同合作将详细映射。 第二，多个BZIP 蛋白质和MYB蛋白质家族的成员将进行测试 彼此之间的协同合作。 第三，将是 确定Z和C-MYB是否可以亲自联系 直接地。 第四，Z蛋白在破坏C-MYB功能中的作用 作为细胞分化的抑制剂。 最后， 将分析C-MYB对EBV复制的影响。 该K08计划计划的其他教育活动包括： 病毒学，细胞功能和分子的研究生水平课程 功能和分子生物学；科学研讨会，包括每周一次 癌症中心大回合科学系列；每周实验室会议； 期刊俱乐部；旅行参加会议以介绍数据并讨论 结果与其他科学家。 通过这些学习工具以及通过 详细介绍合作分子基础的实验工作 在Z和C-MYB之间，该K08奖应为博士提供牢固的基础。 Gutsch开始从事独立医学研究员的职业。