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Title: CHARACTERIZATION OF THE CHROMOSOMAL BINDING SITES AND DIMERIZATION PARTNERS OF THE VIRAL ONCOPROTEIN MEQ IN MAREK'S DISEASE VIRUS TRANSFORMED T CELLS

Author
item LEVY, ALON - UC DAVIS CANCER CENTER
item IZUMIYA, Y - UC DAVIS CANCER CENTER
item BRUNOVSKIS, P - UC DAVIS CANCER CENTER
item XIA, L - UC DAVIS CANCER CENTER
item PARCELLS, M - UNIVERSITY OF ARKANSAS
item REDDY, SANJAY - TEXAS A & M
item Lee, Lucy
item CHEN, H - UC DAVIS CANCER CENTER
item KUNG, H - UC DAVIS CANCER CENTER

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/11/2003
Publication Date: 12/1/2003
Citation: Levy, A.M., Izumiya, Y., Brunovskis, P., Xia, L., Parcells, M., Reddy, S., Lee, L.F., Chen, H.W., Kung, H.J. 2003. Characterization of the chromosomal binding sites and dimerization partners of the viral oncoprotein meq in Marek's disease virus transformed t cells. Journal of Virology. 77:12841-12851.

Interpretive Summary: Marek's disease (MD), a virus-induced cancer-like disease of chickens, is a major disease problem in commercial poultry. Vaccination has dramatically reduced the incidence of the disease, but very little is known about the basic mechanisms involved in the induction of disease. The objective of this research was to study the MEQ gene which is the hallmark for tumor induction. In this study, we provide data for the first time, pertaining to the in vivo partner inside transformed cells. In addition to advancing our understanding as to how Meq functions in T-cells, this report provides new leads to the possible role of Meq in MDV replication. The information obtained from this research is of great interest to scientists and academia as it generated new knowledge on the mechanism of tumor induction and viral replication.

Technical Abstract: Marek's disease virus (MDV) is an acute-transforming a-herpesvirus that causes T-cell lymphomas in chickens. We previously reported the identification of a putative oncogene, Meq, which is encoded only by the oncogenic serotype of MDV. Meq is a latent protein, consistently expressed in MDV-transformed lymphoblastoid cells and tumor cells. Meq has a bZIP (basic-leucine-zipper) structure resembling the family of Jun/Fos. To date, the mechanism whereby Meq transforms T cells remains poorly understood. In this study, we explore the properties of Meq as a transcriptional factor. We analyzed Meq's dimerization partners and its target genes in MSB-1, an MDV-transformed T-cell line. Using in vitro assays, we first demonstrated Meq's potential to dimerize with a variety of bZIP proteins. We then identified Jun as the primary dimerization partner of Meq. They are found to be co-localized in the nucleus, and co-recruited to promoters with AP-1 sequences. Using chromatin immuno-precipitation, we scanned the entire MDV genome for Meq binding sites and found three regions that were enriched with Meq binding: the MDV lytic replication origin, the promoter for Meq and the promoter for ICP4. Transactivation assays using the above promoters showed that Meq/Meq homodimers exhibited repression activity, whereas Meq/Jun heterodimers showed activation activity. Finally, we were able to show by ChIP that Meq is recruited to the IL-2 promoter in a region encompassing an AP-1 site. Thus, in addition to providing general knowledge about the transcriptional properties of Meq, our studies revealed for the first time the ability of Meq to interact with the latent MDV and host genomes. The implications of our findings in the context of viral latency and transformation will be discussed.