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.
