Our studies suggest that p53 is an active oncogene that contributes to tumorigenic conversion. We found that transfection of a functional gene into p53 nonproducer cells which have an inactivated p53 gene reconstitute p53 expression. This genetic manipulation changed the phenotype of these regressing tumor cells into cells that develop lethal tumors. Moreover, cotransfection of the p53 gene with the ras oncogene induced the appearance of transformed foci in primary embryonic rat cells. These findings suggest that the p53 gene plays a causal role in tumorigenicity and as such can be classified as an oncogene. The understanding of the molecular mechanism responsible for the activation of this protein in human and mouse tumor cells and its function in correlation with other oncogene proteins in the malignant process remains unsolved. Our approach to answering these questions can be broken down as follows: (1) activation of p53 at the genomic level will be done by comparing structure and function of p53 genes of transformed and nontransformed cells; (2) activation of p53 at the transcriptional level will be done by comparing structure and function of various p53 cDNA clones of transformed and nontransformed cells; (3) the role of p53 in differentiation and development of normal tissues, and its possible function in the development of tumors in vivo, will be studied by p53 transfection into bone marrow cells that will be transferred into irradiated mice; and (4) the human p53 gene will be studied by transfection of a functional p53 gene into p53 nonproducer HL-60 cells which have an amplified c-myc gene. This may yield indications as to the possible relationship between these proteins and their function in the differentiation of those cells. (X)
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