MOLECULAR BASIS OF INHERITED CANCER SYNDROMES

遗传性癌症综合征的分子基础

• 批准号: 6198230
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-08-23 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6198230
• 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 突变在一些 Li-Fraumeni 综合征 (LFS) 患者中遗传，是许多不同来源肿瘤形成的关键事件。然而，最近的数据表明，其他基因改变也会导致 LFS 典型的癌症易感性。该基因座的定位应该有助于深入了解导致不同肿瘤发生的其他遗传事件。此外，由于 82% 遗传 p53 突变的 LFS 患者遗传了 p53 错义突变，因此我们创建了一个小鼠模型，其中在内源性 p53 基因的第 172 位氨基酸处含有 arg 取代。该突变对应于 6% 的人类肿瘤中 175 位氨基酸发生改变的热点突变。比较小鼠中的 p53 错义和无效等位基因将有助于深入了解 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，可能会改变 p53 功能的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。 p53 的修饰符 mop 1 在本研究中也将是 mappe4d。