Function of the alternatively spliced p53 gene

选择性剪接 p53 基因的功能

• 批准号: 3475-2009
• 负责人: Matlashewski, Gregory
• 金额: $ 2.33万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=419729
• 关键词: Function; alternatively; spliced; p53; gene

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.

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 被认为是肿瘤抑制因子的原型，因为基因工程 p53 敲除小鼠在生命早期就患有多种肿瘤，但其他方面均正常，p53 基因种系突变的人类家族非常容易患癌症，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 表达缺失，其原因仍知之甚少。 p53 蛋白是一种 DNA 结合转录反式激活蛋白，介导细胞基因的表达，其产物会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抵抗力。在 NSERC 的支持下，我们发现人类 p53 基因的选择性剪接会导致 p53 N 端截短形式的表达，称为 deltaNp53(p47)，它能够与全长 p53 相互作用并抑制全长 p53。 该提案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体 p53 相似，更一般地说，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突变的 p53。