The development of a tumor is a multistage process involving multiple genetic aberrations. The p53 tumor suppressor gene is one of the most frequently altered genes in a wide variety of tumor types. More than 50% of human cancers contain alterations in the p53 gene. Mutation is often accompanied by deletion of the second allele, resulting in the elimination of wild-type p53 activity, and leads to a large accumulation of the mutant form of p53 protein in cells. p53 mutations have been associated with poor prognosis in certain cancer patients and are claimed to increase resistance to gamma-irradiation and chemotherapeutic drugs, to increase malignancy of tumor cells, or to induce genomic instability. However, the precise role of mutant p53 in highly malignant tumor cells remains to be elucidated. To identify a new key molecule involved in the gain-of-function of p53 is essential in elucidating the molecular process. We have identified Daxx, an apoptogenic and transcriptional co-repressor protein, as a potential signal acceptor molecule of mutant p53 in cellular stress-responses. Mutant p53 binds to Daxx and inhibits Daxx-dependent stress responses. The long-term goal of this project is to understand the underlying mechanisms of how mutant p53 may contribute to the transformation of human cells to the highly malignant stage as a gain-of-function, with particular emphasis on the mutant p53-Daxx interaction. The results of these studies will be especially beneficial to the understanding of the nature of highly malignant tumors. These studies will also provide additional insights regarding the growth regulation and tumorigenesis in general.
