Loss of wild-type p53 function is thought to be a major factor in resistance to cancer therapy. The fact that most tumors continue to express mutant p53 protein suggests that reactivation of the tumor suppressor function in mutant p53 proteins could restore sensitivity to currently available therapies. p53's capacity to activate gene expression is determined selective binding to DNA sequences and this may be influenced by its association with p53 associated factors (PAFs). Several PAFs that combine with the temperature sensitive p53val35 protein in distinct complexes have been found to exhibit different DNA binding specificities. Furthermore, loss of p53val35 DNA binding activity correlated with loss of association with PAFs, suggesting that PAFs regulate p53 activity by modulating its DNA binding specificity. It is hypothesized that formation of unique complexes containing p53 and one or more PAFs may restore normal p53 function and cell sensitivity to anti-cancer therapies. The objective of this application is to characterize p53/PAF complexes, to elucidate their biological function, and to study the consequences for response to anti-cancer drugs and radiation. To accomplish this, studies will 1) identify the components of distinct p53/PAF complexes and determine whether PAFs can modulate p53 DNA binding, 2) establish whether DNA tumor virus antigens interfere with p53/PAF interactions, 3) characterize PAF protein expression in normal and tumor derived cell lines, and 4) generate PAF specific antibodies and clone PAF cDNAs.
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