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

阐明p53依赖性细胞凋亡机制及其在癌症治疗开发中的应用

基本信息

批准号：
15390110
负责人：
ARAKAWA Hirofumi
金额：
$ 4.93万
依托单位：
National Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

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.

为了阐明p53依赖性细胞凋亡的机制，我们试图识别新的p53靶基因参与细胞凋亡，并进行了这两年的功能分析。最终，我们在2004年和2005年发表了五篇论文，以报告结果。我们已经确定了两个新的p53靶基因，STAG 1和ALDH 4。STAG 1最初被分离为p53- 121 F的特异性靶点，p53- 121 F是p53的活化形式，并且它也被证明介导p53依赖性凋亡。ALDH 4也是编码线粒体蛋白的p53靶基因，但它通过调节脯氨酸代谢负介导p53依赖性凋亡，这意味着它在细胞存活中的作用。此外，我们评估了p53 AIP 1的体内肿瘤抑制活性，该基因之前被鉴定为介导p53依赖性细胞凋亡的p53靶基因。我们的实验表明，腺病毒介导的p53 AIP 1基因转移到肿瘤中可显著抑制肿瘤的生长。这一结果表明，凋亡p53靶基因将取代p53成为癌症治疗的有前途的工具。此外，我们发现轴突导向分子包括p53 RDL 1/UNC 5 B和netrin-1参与p53调节的细胞凋亡。也就是说，在没有netrin-1的情况下，p53 RDL 1/UNC 5 B诱导细胞凋亡，而在netrin-1存在的情况下，它阻断p53诱导的细胞凋亡，基于此，我们提出了一个新的p53调控的细胞凋亡模型。总之，我们在该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，此外，它们还为开发新的癌症疗法提供了可能性。