The Isoforms of the p53 Protein
The Isoforms of the p53 Protein
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DOI：
10.1101/cshperspect.a000927
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发表时间：
2010-03-01
影响因子：
7.2
通讯作者：
Bourdon, Jean-Christophe
中科院分区：
文献类型：
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作者：
Khoury, Marie P.;Bourdon, Jean-Christophe
p53是一种转录因子，在维持遗传稳定性中起关键作用，因此可预防癌症形成。它属于由p53，p63和p73组成的基因家族。p63和p73基因具有双基因结构，在内含子3中具有内部启动子，并且与选择性剪接一起，可以分别表达6种和29种mRNA变体。这种复杂的表达模式以前没有被描述为p53基因，这与我们对p53基因家族进化的理解不一致。因此，我们重新审视了人类p53基因结构，并确定它编码9种不同的p53蛋白亚型，因为选择性剪接，选择性启动子的使用，和选择性的翻译起始位点。因此，人类p53基因家族（p53、p63和p73）具有双重基因结构。我们确定，在果蝇和斑马鱼p53基因的双重基因结构是保守的。双重基因结构的进化保守性表明p53亚型在p53肿瘤抑制活性中起重要作用，我们和其他人已经确定p53亚型可以通过启动子和应激依赖性方式调节p53转录活性来调节细胞命运结果。我们还发现，p53亚型在几种类型的人类癌症中异常表达，这表明它们在癌症形成中起着重要作用。p53亚型表达的测定可能有助于将临床结果与p53状态联系起来，并改善癌症患者的治疗。
p53 is a transcription factor with a key role in the maintenance of genetic stability and therefore preventing cancer formation. It belongs to a family of genes composed of p53, p63, and p73. The p63 and p73 genes have a dual gene structure with an internal promoter in intron-3 and together with alternative splicing, can express 6 and 29 mRNA variants, respectively. Such a complex expression pattern had not been previously described for the p53 gene, which was not consistent with our understanding of the evolution of the p53 gene family. Consequently, we revisited the human p53 gene structure and established that it encodes nine different p53 protein isoforms because of alternative splicing, alternative promoter usage, and alternative initiation sites of translation. Therefore, the human p53 gene family (p53, p63, and p73) has a dual gene structure. We determined that the dual gene structure is conserved in Drosophila and in zebrafish p53 genes. The conservation through evolution of the dual gene structure suggests that the p53 isoforms play an important role in p53 tumor-suppressor activity.We and others have established that the p53 isoforms can regulate cell-fate outcome in response to stress, by modulating p53 transcriptional activity in a promoter and stress-dependent manner. We have also shown that the p53 isoforms are abnormally expressed in several types of human cancers, suggesting that they play an important role in cancer formation. The determination of p53 isoforms' expression may help to link clinical outcome to p53 status and to improve cancer patient treatment.