MAREK'S DISEASE VIRUS MEQ TRANSFORMS CHICKEN CELLS VIA THE V-JUN TRANSCRIPTIONAL CASCADE: A CONVERGING TRANSFORMING PATHWAY FOR AVIAN ONCOVIRUSES

Authors: LEVY, ALON - UC DAVIS - CALIFORNIA; GILAD, OREN - UC DAVIS - CALIFORNIA; XIA, LIANG - UC DAVIS - CALIFORNIA; IZUMIYA, YOSHIHIRO - UC DAVIS - CALIFORNIA; CHOI, JONATHAN - UC DAVIS - CALIFORNIA; TSALENKO, ANYA - AGILENT LAB, PALO ALTO; YAKHINI, ZOHAR - AGILENT LAB, PALO ALTO; Witter, Richard; Lee, Lucy; CARDONA, CAROL - UC DAVIS - CALIFORNIA; KUNG, HSING-JIEN - UC DAVIS - CALIFORNIA

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/8/2005
Publication Date: 10/3/2005
Citation: Levy, A.M., Gilad, O., Xia, L., Izumiya, Y., Choi, J., Tsalenko, A., Yakhini, Z., Witter, R.L., Lee, L.F., Cardona, C., Kung, H. 2005. Marek's disease virus MEQ transforms chicken cells via the v-jun transcriptional cascade: a converging transforming pathway for avian oncoviruses. Proceedings of the National Academy of Sciences. 102:14831-14836.

Interpretive Summary: Marek’s disease (MD), a virus-induced cancer-like disease in chickens, is considered 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 molecularly characterize Marek’s disease virus (MDV) so that successful programs to control the disease can be developed. We have discovered an unique MDV gene (genetic building blocks) termed Meq which was shown to be involved in tumor induction. In this paper, we found that Meq definitively transforms a chicken cell line, DF-1. Using two modern techniques, (micro-array and RT-PCR), we have identified several interacting partners of Meq in the pathway of cellular transformation. This important information will helps scientists in academia better understand the function of this viral gene. Undoubtedly, it will help industry with a possible vaccine for better control of the disease.

Technical Abstract: Marek’s disease virus (MDV) is a highly pathogenic and oncogenic herpesvirus of chickens. MDV encodes a basic leucine-zipper (bZIP) protein, Meq (MDV EcoQ). The bZIP domain of Meq shares homology with Jun/Fos, while the transactivation/repressor domain is entirely different. Increasing evidence suggests that Meq is the oncoprotein of MDV. The mechanism whereby Meq transforms chicken cells remains, however, completely unknown. Taking advantage of the DF-1 chicken embryo fibroblast transformation system, a well-established model for studying avian sarcoma and leukemia oncogenes, we probed the transformation properties and pathways of Meq. We found that Meq transforms DF-1, with a cell-morphology akin to v-Jun and v-Ski transformed cells, and protects DF-1 from apoptosis. Significantly, using micro-array and RT-PCR analyses, we have identified up-regulated genes such as JTAP-1, JAC and HB-EGF, which belong to the v-Jun transforming pathway. In addition, c-Jun was found to form stable dimers with Meq and colocalize with it in the transformed cells. RNAi to Meq and c-Jun down modulated the expression of these genes, and reduced the growth of the transformed DF-1, suggesting that Meq transforms chicken cells by pirating the Jun pathway. These data suggest that avian herpesvirus and retrovirus oncogenes utilize a similar strategy in transformation and oncogenesis.