The goal of this proposal is to study the effects of a series of oncogenes when expressed in a specific cell type of transgenic mice, namely the insulin producing beta cells of the endocrine pancreas. These are epithelial cells which are central to the maintenance of proper carbohydrate balance. It is expected that this analysis will contribute to our knowledge of the properties of oncogenes, which in large part has resulted from assaying their effects on cells cultured in vitro. The specific experimental design is to target oncogene expression to the beta cells using the insulin gene regulatory region. We have already established that these sequences are capable of directing expression of a linked oncogene (the early region of SV40) exclusively to the beta cells of the pancreas. Among the new hybrid oncogenes to be examined are Hras, E1A, v-myc, cmyc, p53, v-src, and v-erbB. The consequences of oncogene expression will be evaluated from several perspectives: 1) does targeted expression of individual oncogenes produce tumors, and at what rate, and in what number per animal, 2) what are the effects when pairs of hybrid oncogenes are combined by mating individual transgenic mice in a genetic complementation assay; 3) do individual oncogenes or specific pairs of oncogenes cause metastasis of the beta cell tumors, and 4) do certain insulin promoted oncogenes cause diabetes rather than cancer, as a direct or indirect result of their expression in beta cells. The tumors will be characterized with respect to cellular and chromosomal anatomy, alterations in endogenous gene expression, and the possibility that secondary mutations occurred during oncogenesis. In addition, the immunological and physiological consequences of oncogene expression in the islets of Langethans will be evaluated.
