RAS GENE MUTATION TIME AND STRUCTURE IN MOUSE LYMPHOMAS

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We will continue to study the model system of murine induced thymic lymphomas by carcinogenic agents. Since we have already demonstrated that K and N-ras oncogenes are consistently associated with these tumors, we will concentrate first in the analysis of the balance or imbalance between the mutated, allele and its normal counteerpart in these tumors. We will study also the structure of the mouse N-ras oncogene determining the number and location of its untranslated exons and their function using in vitro mutagenesis and gene transfer. We will approach the controversial problem of ras being an early or late event in tumorigenesis by using transplantation of preleukemic cells from a single donor into several recipients and analyzing if the subseqent tumors have all the same oncogene mutation. Finally, and conceptually related to the previous experiments we will attempt to create transgenic mice with an activated N-ras oncogene, under the influence of an inducible promoter, to determine if it can, alone or in combination with other factors, produce malignancies when it is timely induced to express.