The long-term objective of these studies is to understand how retroviruses that do not possess oncogenes are able to cause neoplastic diseases. These neoplasias typically occur in multiple stages involving long latency periods similar to most human cancers. The early events that are critical for the development of tumors are especially difficult to study. The murine leukemia viruses (MLVs) provide an ideal model system to identify these early events because they have a well-delineated preleukemic period. In our studies of the early stages of thymic lymphoma development in mice, we demonstrated that infection by a mink cell focus-forming (MCF) MLV led to an enhancement of apoptosis of thymic lymphocytes. Recent in vitro studies have shown that virus infection can directly induce apoptosis in certain cells. To better understand the role of apoptosis in tumorigenesis by MCF13 MLV, we propose to elucidate the mechanism by which this process occurs.
Aim 1 examines the requirement for apoptosis in MCF MLV-induced lymphomagenesis. MLVs with different pathogenic and cytopathic properties will be compared in in vitro and in vivo studies. The role of antiapoptotic proteins in rescuing virus-infected cells from apoptosis will be defined.
Aim 2 elucidates the mechanism by which glycoprotein binding to the MCF MLV receptor (XPR1) induces apoptosis. Immunoadhesins comprised of the MCF glycoprotein will be employed. Identification of the apoptotic signaling pathway involved in glycoprotein-receptor interactions will be made.
Aim 3 focuses on the role of receptor polymorphism in virus-mediated cell killing. XPR1 proteins cloned from different animals will be tested for their ability to mediate cell killing. Hybrid receptor proteins will be made to identify the regions of XPR1 that are essential for cytopathicity. The results of these studies will enhance our understanding of the role of apoptosis in the development of neoplastic disease.
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