This study is aimed at investigating the molecular biology of the p53 oncoprotein and its relevance for normal and aberrant growth control. In light of present ambiguities, the precise sequence and transforming potential of wild type p53 will be verified by analysis of normal genomic DNA and new genomic DNA clones. The in vivo effects of point mutations present in p53 from tumor-derived Meth A cells will be investigated by assaying for tumorgenicity in nude mice. The concept that mutations in p53 are a common feature in certain tumor types will be tested by studying in detail the protein and its gene in a series of chemically induced fibrosarcomas. If mutant, transformationally-activated p53 species are frequently observed, this will strongly argue for a direct role of p53 in carcinogenesis. In parallel, transcriptional regulation of p53 gene expression will be studied employing the cloned 5' flanking regions of mouse, rat and human p53 genes. This should provide information on the structural DNA elements and the cellular factors that play a role in controlling p53 gene activity in various systems. Another possible type of control will be explored in Friend cells, where structural alterations in p53 mRNA appear to be induced during erythroid differentiation. To better understand the biochemical activities of p53, attempts will be made to isolate and study genes whose expression may be modulated by p53, as well as to isolate cellular DNA sequences specifically interacting with this protein and test for its possible involvement in DNA replication. Finally, the concept that abrogation of p53 synthesis may be advantageous for certain tumor cells will be studied by introducing p53 expression plasmids into p53 negative human SCLC cells.