Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s
Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s
复制标题
DOI：
10.1158/0008-5472.can-04-2935
复制
发表时间：
2005-03-15
期刊：
影响因子：
11.2
通讯作者：
Ishioka, C
中科院分区：
文献类型：
--
作者：
Kakudo, Y;Shibata, H;Ishioka, C
肿瘤抑制因子p53依赖的细胞凋亡被认为是人类肿瘤发生中最重要的肿瘤抑制功能之一。然而，p53依赖性细胞凋亡的主要机制是依赖于反式激活还是不依赖于反式激活仍不清楚。使用179突变p53不同的转录活性不同的p53结合序列在酵母中，我们评估了它们的序列特异性转录活性的6个p53靶基因和它们的能力，诱导凋亡的Saos-2细胞。这些突变型p53也代表了它们反式激活靶基因和诱导细胞凋亡的能力的多样性。我们鉴定了17个突变型p53，其诱导细胞凋亡的能力比野生型p53更上级，其倾向于聚集在残基121或290至292处。在所检测的任何单个靶基因上，两种功能性质之间没有显著相关性。此外，17个突变型p53的不同的转录活性的层次聚类分析没有被归类在一个特定的集群，表明这些突变型p53的下游基因的转录活性不相似。这些结果表明，反式激活依赖的细胞凋亡并不总是发挥主要作用，p53依赖的细胞凋亡，间接支持的反式激活非依赖性机制的重要作用。
Tumor suppressor p53-dependent apoptosis is thought to be one of the most important tumor-suppressive functions in human tumorigenesis. However, whether the major mechanism underlying the p53-dependent apoptosis is transactivation dependent or independent remains unclear. Using 179 mutant p53s with diverse transcriptional activities for distinct p53-binding sequences in yeast, we evaluated both their sequence-specific transcriptional activities on six p53 target genes and their ability to induce apoptosis in Saos-2 cells. These mutant p53s also represented diversity in their ability to both transactivate target genes and induce apoptosis. We identified 17 mutant p53s with superior ability to induce apoptosis than wild-type p53 that tend to cluster at residues 121 or 290 to 292. There was no significant correlation between the two functional properties on any single target gene examined. Furthermore, the 17 mutant p53s were not classified in a specific cluster by hierarchical cluster analysis on their diverse transcriptional activities, indicating that these mutant p53s were not similar in the transcriptional activity of downstream genes. These results suggested that transactivation-dependent apoptosis does not always play a major role in p53-dependent apoptosis, indirectly supporting the importance role of the transactivation-independent mechanism.