The c-myc gene is among the most frequent sites of mutation for any oncogene in human cancer. Approximately 15 percent of all cancers exhibit amplification of the c-myc gene and about 25 percent of breast cancers have similar mutations. Chromosomal translocations at c-myc occur in 100 percent of Burkitt's lymphomas, as well as in the related mouse plasmacytomas. Although these gross chromosomal abnormalities have been recognized for many years, it has only recently become apparent that missense mutations can also play a major role in the oncogenic activity of c-myc, and more that 60 percent of Burkitt's and AIDS- associated lymphomas have mutations that alter the protein structure of the already translocated c-myc gene. A major question confronting the c-myc field (and nuclear oncogenes in general) is which cellular genes are targeted ty the oncoprotein to mediate its function in cell cycle progression or apoptosis. Of broader interest is how the c-myc signaling pathway is interwoven with the signals emanating from other oncogenes. The specific goals of this project are to: 1) Dissect the role of the c-Myc protein in signaling pathways leading to cell growth or apoptosis. They will use novel cell lines that are completely deficient in endogenous c-Myc protein expression through the knockout of both chromosomal alleles. The role of phosphorylation in c-Myc activity and the function of a newly isolated Myc-interacting factor, TIP49, will also be investigated. 2) Analyze the Myc-dependent expression of previously identified as well as novel target genes. Novel targets that are linked to specific biological activities of c-Myc will be selected for by subtractive or differential display approaches. 3) Determine the functional role of mutations in the N-terminal domain of the c-Myc oncoprotein that are found in the majority of Burkitt's lymphomas. Cell lines that are reconstituted with only mutant or wt c-Myc protein expression will allow the unambiguous analysis of different functions. The relative activity of different c-Myc mutants in both B cells and fibroblasts will be analyzed.
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