Function of the alternatively spliced p53 gene

人类p53基因是研究最深入的基因之一，因为它是肿瘤抑制基因的原型。P53被认为是肿瘤抑制的原型，因为基因工程P53零敲除小鼠在生命早期获得多个肿瘤，但在其他方面是正常的，P53基因发生种系突变的人类家族极易患癌症，P53是人类癌症中最常见的突变基因。有趣的是，大多数肿瘤表达p53的突变形式，而不是p53的表达缺失，其原因尚不清楚。p53蛋白是一种DNA结合转录反激活因子，介导细胞基因的表达，其产物损害细胞周期并诱导细胞凋亡。正常细胞p53功能的丧失有利于肿瘤发生，也使肿瘤细胞对化疗和放疗产生耐药性。在NSERC的资助下，我们发现人类p53基因的选择性剪接导致了n端截断形式的p53的表达，称为deltaNp53(p47)，它能够与全长p53相互作用并抑制p53。该提案中需要解决的一个主要问题是deltaNp53（p47）的行为是否与肿瘤衍生的突变型p53相似，以及更普遍的deltaNp53（p47）的功能是什么。这项研究可以更好地理解为什么许多肿瘤表达p53突变体。

The human p53 gene is among the most intensely studied because it is the prototype tumor suppressor gene. p53 is considered the prototype tumor suppressor because genetically engineered p53 null knockout mice acquire multiple tumors very early in life but are otherwise normal, human families with germline mutations in the p53 gene are highly cancer prone, and p53 is the most common mutated gene in human cancers. Interestingly, most tumors express mutant forms of p53 as opposed to loss of p53 expression and the reason for this remains poorly understood. The p53 protein is a DNA binding transcriptional transactivator that mediates the expression of cellular genes whose products impair the cell cycle and induce apoptosis. Loss of normal cellular p53 function favors tumorigenesis and also renders tumor cells resistant to chemo- and radiotherapy. With the support of NSERC during our last funding period, we discovered that alternative splicing of the human p53 gene results in the expression of a N-terminal truncated form of p53 termed deltaNp53(p47) which is capable of interacting with and inhibiting the full length p53. A major question to be addressed in this proposal is whether deltaNp53(p47) behaves similar to tumor derived mutant p53 and more generally what is the function of deltaNp53(p47). This research could provide a better understanding of why many tumors express a mutant p53.