Clarification of the mechanism for p53-dependent apoptosis and its application for the development of cancer therapies

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To clarify the mechanism for p53-dependent apoptosis, we have tried to identify new p53-target genes involved in apoptosis, and we have carried out their functional analyses for these two years. Eventually, we have published five papers in 2004 and 2005 in order to report the results. We have identified two new p53-target genes, STAG1 and ALDH4. STAG1 was initially isolated as a specific target of p53-121F, an activated form of p53, and it was also shown to mediate p53-dependent apoptosis. ALDH4 is also a p53-target gene encoding a mitochondrial protein, but it negatively mediates p53-dependent apoptosis through the regulation of a proline metabolism, implying its role in cell survival. In addition, we evaluated the tumor suppressive activity of p53AIP1 in vivo, which was previously identified a p53-target gene that mediates p53-dependent apoptosis. In our experiments adenovirus-mediated p53AIP1 gene transfer into tumors remarkably induced growth suppression of tumors in vivo. This result suggests that apoptotic p53-target genes would become promising tools for cancer therapies instead of p53. Moreover, we have discovered that axon-guidance molecules including p53RDL1/UNC5B and netrin-1 are involved in p53-regulated apoptosis. That is, in the absence of netrin-1,p53RDL1/UNC5B induces apoptosis, whereas it blocks p53-induced apoptosis in the presence of netrin-1,based on which we proposed a new model for p53-regulated apoptosis. Taken together, our findings in this project greatly contributed to our understanding of the mechanism for p53-dependent apoptosis, and in addition they provided a possibility for the development of new cancer therapies.