This proposal describes experiments that will characterize DNA fragments in the human genome with homology to the myc proto- oncogene family. Cellular proto-oncogenes are associated with cancer, a disorder characterized by potentially unlimited growth, and have provided an experimental framework in which to explore the complex processes of normal growth regulation. The c-myc proto- oncogene has been studied extensively and the correlation of its aberrant expression with various malignancies is clear. Little is known, however, about the normal function of this gene or the role it plays in oncogenesis. c-myc is a member of a family of proto- oncogenes including N-myc, L-myc and a newly isolated gene described in this proposal, H-myc1, which share nucleotide, protein sequence and functional homology. A comparison of the structure and function of these genes may allow us to better understand their specific contribution in growth control and to delineate further the events that transform a normal cell into a malignant cell. Experiments planned will characterize H-myc1 and an additional myc- related sequence. Both of these DNA fragments were isolated by hybridization to oligonucleotide probes corresponding to regions of nucleotide homology in the myc family. Several approaches including gene mapping and tumorigenic capacity in the rat embryo fibroblast assay will be employed. The expression of these new sequences will be analyzed in both normal and malignant tissues. Also, corresponding murine genes will be characterized to facilitate the analysis of mRNAs in tissues not easily obtained from humans. Heteroduplex analysis of human and murine genes, isolation of cDNA clones and CNA sequencing will provide information about the structure of additional myc genes and permit comparisons of coding and regulatory regions. Oligonucleotide probes constructed from additional recently discovered homologous regions will be used in addition to those already prepared to identify, isolate and characterize other potential myc genes.
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