Transformation and Oncogenesis by Jaagsiekte Sheep Retrovirus

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Abstract

Jaagsiekte sheep retrovirus (JSRV) is an exogenous retrovirus of sheep that induces a contagious lung cancer, ovine pulmonary adenocarcinoma (OPA). JSRV is a potent carcinogen in the experimental setting, inducing end-stage tumors at around 6 weeks of age when newborn lambs are inoculated intratracheally. Despite this rapid oncogenesis, inspection of the JSRV genome sequence does not reveal any obvious viral oncogenes. In this review, recent advances in studies of JSRV oncogenic transformation are described. Molecular cloning of an infectious and oncogenic JSRV provirus was instrumental in the studies. DNA transfection of JSRV proviral DNA into mouse NIH3T3 cells results in morphological transformation, indicating that the JSRV genome carries an oncogene. Further experiments identified the JSRV envelope protein as the transforming gene, and a PI3 kinase docking site in the cytoplasmic tail of the transmembrane (TM) protein was shown to be necessary for transformation. Avian DF-1 cells infected with an avian retroviral vector (RCAS) expressing the JSRV envelope protein also undergo tumorigenic transformation. Possible mechanisms of transformation are discussed, and a cooperating role for insertional activation of proto-oncogenes in tumorigenesis is also considered. The transforming potential of the JSRV envelope protein may be necessary for JSRV infection and replication in vivo.