p53 is a cellular protein often found elevated in transformed cells. Recently, p53 has been shown to be capable of transforming primary embryonic cells in cooperation with Ha-ras. This cotransformation system and its modified versions will be employed in order to study the effects of p53 on cell behavior and the molecular mechanisms leading to these effects. Transformants derived by p53 + Ha-ras cotransfection will be analyzed for stability and cell cycle dependence of p53, regulation of endogenous p53, and interrelationship between p53 and c-myc. Special use will be made of inducible p53-specifying constructs, which should enable a rapid switch on and off of p53 synthesis and examination of the direct consequences of such modulations. In parallel, the immortalizing effect of p53 on primary cells will be determined, as will the effects of p53 inactivation (using antisense cDNA vectors) on normal and transformed cells. The possibility that p53 acts as a gene modulator will be studied by cloning mRNA species made in response to p53 activation and searching for specific sites on the corresponding genes capable of interaction with p53. A further aspect will deal with the possible significance of amino acid differences suggested to exist between p53 of normal and transformed cells. To establish the generality of this finding, more clones will be generated from transformed cells and analyzed by nucleotide sequencing. The normal and altered p53 genes will be directly compared for activity following transfection into nontransformed cells. Finally, the possible relevance of p53 to SV40-mediated transformation will be probed by studying the effects of p53 overproduction on the transforming potential of normal and mutant SV40. All these studies will help to elucidate the mode of action of p53 and should be of broader relevance to the understanding of the molecular mechanisms involved in neoplastic transformation. (X)
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