GENES INVOLVED IN PRENEOPLASTIC PROGRESSION

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The aim of this research is to identify and characterize genes involved in the progression of cells from the normal to the neoplastic phenotype in mice and humans. Evidence suggesting the involvement of such genes in animal and human systems has come from the observations that there are irreversible steps in tumor promotion and that animals can be bred for sensitivity to tumor promotion. Genes that specify sensitivity to promotion of neoplastic transformation by tumor promoters in mouse epidermal JB6 cells have been cloned. Two such genes, termed pro-1 and pro-2, have been identified. These differ from each other and from known oncogenes. Pro-1 has been sequenced. The sequence is intronless, shows the consensus sequences needed for transcription and translation and is expected to code for a 7000 dalton protein. Tumor promoter treatment of promotion sensitive (P+) cells produces transient increases in pro-1 RNA levels. Chinese human nasopharyngeal carcinoma cell (CNE) DNA shows both P+ activity (by transfection) and homologs of pro-1 and pro-2 (by Southern blotting). Pro-1 homologs have been cloned from a CNE library and initial assays indicate that they are biologically active for P+ activity. In addition, a novel transforming activity detectable in P+ recipient cells has been found in the DNA of 12-0-tetradecanoylphorbol-13-acetate (TPA) transformed JB6 cells. In the future, these studies will be concerned with understanding pro gene expression and pro gene products and their significance in human and rodent cells. The regulation of pro gene transcription by tumor promoters and antipromoters will be studied. The structure and biological activity of human pro gene homologs will be characterized. Pro-1 proteins will be purified, characterized and localized. A novel transforming gene will be cloned and its mode of regulation by pro genes will be studied.