MOLECULAR BASIS OF INHERITED CANCER SYNDROMES

遗传性癌症综合征的分子基础

• 批准号: 6357985
• 负责人: GUILLERMINA LOZANO
• 金额: $ 27.04万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-27 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6357985
• 关键词: Li Fraumeni syndrome; clinical research; disease /disorder model; genetic mapping; genetic models; human subject; laboratory mouse; lethal genes; molecular oncology; neoplasm /cancer genetics; p53 gene /protein; point mutation

Mutation of p53, inherited in some individuals with Li-Fraumeni Syndrome (LFS), is a critical event in the elaboration of many tumors of diverse origin. Recent data, however, suggest that other genetic alterations also result in the cancer predisposition typical for LFS. The mapping of this locus should yield insight into other genetic events that lead to the genesis of diverse tumor. In addition, since 82% of LFS patients inheriting mutations of p53 inherit a missense mutation in p53, we have created a mouse model containing an arg to his substitution at amino acid 172 of the endogenous p53 gene. This mutation corresponds to the hot spot mutation at amino acid 175 altered in 6% of human tumors. Comparison of p53 missense and null alleles in the mouse will yield valuable insight into the in vivo differences between p53 mutants. Additional genetic events that may modify the ability of p53 to function are suggested by experiments using another mouse model (CE/J) in which heterozygosity or homozygosity at the p53 locus results in embryo lethality. This modifier of p53, mop 1, will also be mappe4d in this study.

p53基因突变，在某些李-弗劳梅尼综合征（LFS）的个体中遗传，是许多不同起源肿瘤的关键事件。然而，最近的数据表明，其他遗传变异也会导致LFS典型的癌症易感性。这个基因座的定位应该会让我们深入了解导致不同肿瘤发生的其他遗传事件。此外，由于82%的LFS患者遗传突变的p53遗传错义突变的p53，我们已经创建了一个小鼠模型，含有一个精氨酸取代他的氨基酸172的内源性p53基因。该突变对应于在6%的人类肿瘤中改变的氨基酸175处的热点突变。在小鼠中比较p53错义和无效等位基因将产生有价值的洞察到p53突变体之间的体内差异。使用另一种小鼠模型（CE/J）进行的实验表明，可能改变p53功能能力的其他遗传事件，其中p53基因座的杂合性或纯合性导致胚胎致死。在本研究中，p53的修饰物mop 1也将是mappe 4d。