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

为了阐明p53依赖性细胞凋亡的机制，我们试图发现新的p53靶基因参与细胞凋亡，并在这两年进行了功能分析。最终，我们在2004年和2005年发表了五篇论文来报告结果。我们已经确定了两个新的p53靶基因，STAG1和ALDH4。STAG1最初是作为p53的活化形式p53- 121f的特异性靶点分离出来的，并且也被证明可以介导p53依赖性的细胞凋亡。ALDH4也是p53靶基因，编码线粒体蛋白，但它通过调节脯氨酸代谢负向介导p53依赖性凋亡，暗示其在细胞存活中的作用。此外，我们在体内评估了p53AIP1的肿瘤抑制活性，该基因先前被鉴定为p53靶基因，介导p53依赖性细胞凋亡。在我们的实验中，腺病毒介导的p53AIP1基因转移到肿瘤中显著诱导肿瘤生长抑制。这一结果表明，凋亡的p53靶基因将成为替代p53的有希望的癌症治疗工具。此外，我们还发现轴突引导分子p53RDL1/UNC5B和netrin-1参与了p53调控的细胞凋亡。即在netrin-1缺失的情况下，p53RDL1/UNC5B诱导细胞凋亡，而在netrin-1存在的情况下，p53RDL1/UNC5B则阻断p53诱导的细胞凋亡，我们在此基础上提出了p53调控细胞凋亡的新模型。综上所述，我们在这个项目中的发现极大地促进了我们对p53依赖性细胞凋亡机制的理解，并且为开发新的癌症治疗方法提供了可能性。

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.