Genetic Aspects Of Viral Oncogenesis

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Abstract

Wild mouse species and inbred strains differ from one another in their susceptibility to the mouse gammaretroviruses and retrovirus-induced diseases. These differences are due to allelic differences in specific mouse chromosomal genes, and we have been engaged in an ongoing effort to identify and characterize several mouse genes involved in this resistance: - We have continued our analysis of a serum lipoprotein factor found in most mice that inactivates leukemia viruses. We have demonstrated that production of this factor is controlled by a single gene. We have mapped this gene to a position on mouse chromosome 10 and eliminated one candidate gene in this region, Apof (apolipoprotein F). We have identified two additional candidate genes and are in the process of characterizing these genes in factor positive and negative mice. We have also generated congenics to determine how presence or absence of this factor affects disease progression in mice with a high incidence of disease. - We have continued our efforts to characterize the resistance gene Rmcf2 originally found in the wild mouse species M. castaneus. This gene is responsible for partial resistance to the highly pathogenic polytropic class of leukemia viruses. We have cloned a chromosomally integrated copy of the viral genome linked to the Rmcf2 locus, and shown that its expression is associated with virus resistance. This suggests that Rmcf2 resistance may be mediated through an interference mechanism. - We have identified two unusual variants of the ecotropic gammaretroviruses that are cytopathic in M. dunni cells and also have altered host range. These phenotypes are due to different amino acid substitutions at the same site in the two viruses. This substitution alters one of the 3 amino acids that form the cell surface receptor binding site. The fact that these 2 viruses cause cytopathic effects in a cell line with a variant receptor gene suggest that the virus-receptor interaction mediates cytopathicity. This conclusion was confirmed by the observation that cytopathicity due to virus infection is seen in stable transfectants expressing this variant receptor but not in transfectants expressing the prototypical receptor. Because evidence also suggests that cytopathicity is affected by inhibitors of glycosylation, we are currently evaluating the role of glycosylation in virus infectivity and cytopathicity. - We have screened a panel of cells derived from divergent wild mouse species for infectivity with a panel of ecotropic mouse gammaretroviruses. These viruses differ substantially in their envelope glycoproteins and show differences in infectivity of these wild mouse cells. Factors that contribute to the observed infectivity differences include receptor polymorphism, differences in glycosylation, variable levels of CAT-1 expression, and a post-receptor block in replication. Finally, we used the resources we developed for mouse genomic analysis and mapping in a study with Dr. Y. Yamada to characterize a novel site member of the Krox family of proteins. We showed that this protein may play an important role as a transcription factor in the cytodifferentiation and amelogenesis of enamel epithelium during tooth development.