Pathogenesis of ovine betaretroviruses

The study of oncogenic retroviruses has been instrumental in elucidating the functions of key cellular proteins involved in cell growth and transformation. Many of the oncogenes found to be active in human cancers were first discovered in avian, murine and feline retroviruses. Moreover, the discovery of the activation of cellular genes upon retroviral insertion into chromosomal DNA has provided a model of oncogenesis similar in mechanism to chromosome translocation and/or gene rearrangement in human tumors. Novel mechanisms of transformation by retroviruses continue to be identified, as evidenced by our discovery of the oncogenic properties of the ovine betaretroviral envelope (Env) proteins, a heretofore-unprecedented finding. Betaretroviruses, of which Jaagsiekte sheep retrovirus (JSRV), Enzootic nasal tumor virus (ENTV), mouse mammary tumor virus (MMTV) and Mason-Pfizer monkey virus (MPMV) are members, are unique in that unlike many of the oncogenic retroviruses, which cause hematopoietic malignancies, viruses in this family are often associated with the development of solid tumors, primarily carcinomas. Research in our laboratory is largely directed towards understanding the molecular pathogenesis of JSRV and ENTV, causative agents of transmissible lung and nasal cancer, respectively, in sheep and goats.  As viral proteins subvert many of the same cellular pathways and checkpoints commonly mutated in tumor cells, these model systems are being used to uncover critical events in the development of lung and nasal cancer.