Many DNA tumor viruses cause tumors by inactivating host tumor suppressors that guard against cellular genomic alterations and/or regulate cell cycle. Stripped of these controls, infected cells cycle more often and accumulate mutations more or less passively. Very recently, however, it has become clear that active viral manipulation of programmed cell death (apoptosis) plays a key role in oncogenesis and in the course of virus infection. We propose to study the pathogenesis of malignant fibromatosis elicited by malignant rabbit fibroma virus (MV) as a function of the virus ability to manipulate apoptosis and cell cycle progression. MV causes disseminated fibromyxoid tumors, severe immune suppression and death. We have found that C7 early viral transcription factor is a major determinant of MV virulence. Infection with MV and transfection with C7 both: (i) upregulate p53, (ii) slow cell cycle and (iii) cause apoptosis. We propose here to define the mechanisms by which MV and C7 elicit apoptosis and the role of apoptosis in the pathogenesis of malignant fibromatosis. These studies will test the following hypotheses: Hypotheses: The ability of MV to elicit apoptosis determines to a large extent its ability to cause disseminated tumors, suppress immune function, and kill susceptible animals. Furthermore, C7 plays a major role in this apoptosis. To test these hypotheses, we will identify the cellular targets and effects on C7- induced apoptosis, and define the signaling pathways involved. Mutant MVs separately incorporating the apoptosis inhibitors Bcl-2 and P35 will be generated. Effects of P35 and Bcl-2 on virus replication, cellular proliferation, lymphocyte function, tumor development, and the course of MV infection will be studied both in vitro and in vivo. The mechanisms whereby C7 elicits apoptosis and modifies cell cycle progression will be determined. Thus, we hope to define the importance of apoptosis to the pathogenesis of malignant fibromatosis, and of C7 to apoptosis. These studies will help elucidate the mechanisms by which viruses may manipulate and subvert cellular survival and death mechanisms to replicate themselves, suppress immune function, and cause tumors.
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