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Analyses and Therapeutic Applications of p53 Family Genes, p53, p51, and p73

p53 家族基因、p53、p51 和 p73 的分析和治疗应用

基本信息

批准号：
11138206
负责人：
IKAWA Shuntaro
金额：
$ 4.8万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11138206/
关键词：
p53 p51 p63 p73 tumor suppressor gene gene therapy chimeric gene promoter

项目摘要

p53 tumor suppressor gene, sensing DNA damage, causes cells to undergo G1-arrestor apoptotic death, thereby playing a critical role in human carcinogenesis. Searching for p53 related genes, I successfully isolated p51 along with p73. In addition to their structural resemblance, they exhibited functional similarities to p53. I obtained following result by analyses of p53 family genes. (1) Analyses using chimeric gene constructs : Chimeric genes composed of p51, p53, and p73 coding sequences by connecting their major functional domains, proved to have striking preference over various promoters with variety of properties. In an attempt to take advantage of these properties suitable for gene therapeutic application and functional analyses, I constructed adenoviral version. (2) Analyses of genomic p51 and p73 : Genomic sequencing analyses of nearly entire of p51 and p73, revealed striking similarity. Two independent promoter regions of p51, TAp51 andΔNp51 promoters, were identified. I also started to clone and/or analyze transactivtor gene responsible for transcription of ΔNp51, since the ΔNp51 promoter was narrowed down to two 10 bp regions. (3) Analyses of newly identified isoforms : I newly identified various isoforms of p51 and p73. Most importantly of ΔNp73, which proved to exert dominant negative function against TAp73 and p53. (4) Analyses of p51, p73 protein regulation : I found that p51 was not regulated by MDM2, a major regulator of p53 protein activity. Nevertheless, observation of strong ubiquitination of p51 led us to investigate and clone MDM2-like gene capable of regulating p51.

p53肿瘤抑制基因，感应DNA损伤，导致细胞经历G1期凋亡，从而在人类肿瘤发生中起关键作用。在寻找p53相关基因的过程中，我成功地将p51沿着p73分离出来。除了结构相似外，它们还表现出与p53的功能相似性。通过对p53家族基因的分析，得到以下结果。(1)使用嵌合基因构建体的分析：由p51、p53和p73编码序列通过连接它们的主要功能结构域组成的嵌合基因被证明对具有各种特性的各种启动子具有显著的偏好。为了利用这些特性进行基因治疗和功能分析，我构建了腺病毒版本。(2)基因组p51和p73的分析：几乎整个p51和p73的基因组测序分析显示出惊人的相似性。鉴定了p51的两个独立的启动子区域，TAp 51和Δ Np 51启动子。由于Δ Np 51启动子被缩小到两个10 bp的区域，我也开始克隆和/或分析负责Δ Np 51转录的反式激活因子基因。(3)新鉴定的亚型分析：我新鉴定了p51和p73的各种亚型。最重要的是Δ Np 73，其被证明对TAp 73和p53发挥显性负功能。(4)p51、p73蛋白调节分析：发现p51不受p53蛋白活性的主要调节因子MDM 2的调节。然而，观察到p51的强烈泛素化使我们研究并克隆了能够调节p51的MDM 2样基因。