Oncogenesis by Jaagsiekte Sheep Retrovirus

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DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer mortality in the United States. Bronchiolo-alveolar carcinoma (BAC) accounts for as much as 25 percent of lung cancer; the incidence of BAC has been increasing, and it is not etiologically linked to tobacco smoke. Thus, there is need for research in BAG. Sheep provide a unique model for BAC: ovine pulmonary carcinoma (OPC) that is caused by an exogenous retrovirus, jaagsiekte sheep retrovirus (JSRV). Recently, we isolated an infectious and oncogenic molecular clone of JSRV. The mechanism by which JSRV causes OPC is of great interest. In preliminary experiments, we have found that JSRV contains direct transforming activity, as measured by DNA transfection assays in murine NIH3T3 cells. The transforming activity has been localized to the JSRV env gene. Other investigators have mapped the JSRV cell receptor to region of human chromosome 3p21.3, an area that shows loss of heterozygosity (LOH) in human tumors, including lung cancer. This raises the possibility that JSRV Env protein may cause oncogenic transformation by binding to, and interfering with, the function of a tumor suppressor gene. In the proposed experiments, we will explore the mechanism of oncogenic transformation induced by JSRV env. Specifically, we will: 1) Identify the region of JSRV Env protein responsible for transformation; 2) Identify the cellular protein(s) that interact with the critical region of Env; 3) Examine the role of Env protein in oncogenesis in vivo and develop transgenic mouse models for the disease; and 4) Study the mechanism of JSRV env-induced transformation. These experiments will give new insights into oncogenesis by JSRV (which is an important veterinary disease in high endemic regions), and they may shed light on the mechanism of BAG oncogenesis.