COOPERATION BETWEEN C-MYB AND THE EBV Z TRANSACTIVATOR

这是为David Gutsch博士申请K08奖项的申请表，旨在 进一步发展他在分子生物学方面的技能，并提供 经验是肿瘤学的领域，特别是在研究 致癌基因。他之前在莱恩伯格癌症中心接受的培训 北卡罗来纳大学专注于爱泼斯坦-巴尔的基因调控 病毒(EBV)复制。EBV是一种重要的人类病原体，它能引起 Burkitt淋巴瘤、鼻咽癌和淋巴瘤 免疫功能受损的宿主。古奇博士及其同事的初步工作 已经确定了一种重要的EB病毒之间的相互作用-早期 蛋白质、Z和c-myb原癌基因。这两种蛋白质， 作为转录反式激活因子发挥作用，协同增强 另一方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 引发病毒生产性感染。正常情况下需要C-Myb 造血发育和正常的细胞周期进程。这 新的交互作用可能通过以下方式潜在地增强EBV潜伏期的中断 Z，并且可以用作bZIP之间的一般交互的示例 蛋白质和Myb家族的成员。这项提案中的实验 将扩展这些初步发现，建立通用的 BZIP/Myb交互，制定这样一个 相互作用，并探索其潜在的生物相关性。首先， Z和c-Myb蛋白的精确结构域 将详细绘制协同合作图。第二，多个bZIP 将对蛋白质和Myb蛋白质家族的成员进行测试 相互之间的协同合作。第三，它将是 已确定Z和c-Myb是否可以物理接触 直接去吧。第四，Z蛋白在破坏c-Myb功能中的作用 作为一种细胞分化的抑制物，将会被研究。最后， 将分析c-Myb对EBV复制的影响。 为该K08计划计划的其他教育活动包括： 病毒学、细胞功能和分子方面的研究生课程 功能和分子生物学；科学研讨会，包括每周一次 癌症中心大巡回科学系列；每周实验室会议； 日记俱乐部；以及出差参加会议，介绍数据和讨论 与其他科学家的研究结果。通过这些学习工具和通过 详细说明合作的分子基础的实验工作 在Z和c-Myb之间，这个K08奖项应该为Dr. Gutsch开始了作为一名独立医学研究人员的职业生涯。

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.