REGULATION OF P53 FUNCTION BY SV40 T ANTIGEN

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Alteration of the function of the p53 gene product through mutagenesis causes normal cells to become cancerous. Several viruses, including SV40, encode gene products that bind to p53, presumably to subvert its normal function as a tumor suppressor. Several aims will be pursued in order to study the structure and function of p53 and their regulation by SV40 T antigen. (1) The DNA binding properties of p53 will be investigated in order to understand (i) the DNA sequences to which it binds, (ii) the mode by which it contacts DNA and (iii) the region of the p53 protein that is necessary for binding to DNA. (2) The role of p53 as a transcriptional activator will be investigated. The ability of p53 to regulate transcription alone or in concert with other transcription factors will be examined. (3) The ability of p53 to inhibit DNA replication, by binding to SV40 T antigen or by binding to DNA, will be characterized in vitro and in vivo. (4) The mode by which SV40 T antigen, either alone or when bound to the RB protein, represses the DNA binding and transcriptional activation properties of p53 will be studied. (5) Cellular proteins that bind to and interact functionally with p53 will be identified. (6) The properties and role of Xenopus laevis p53 in oocytes and early embryos will be examined. It is hoped that insight into the functions of viral tumor antigens and cellular tumor suppressors will be gained.