TUMORIGENICITY OF DIFFERENT P53 MISSENSE MUTATIONS

不同 P53 错义突变的致瘤性

• 批准号: 2465352
• 负责人: GERALD P HOLMQUIST
• 金额: $ 11.25万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2465352
• 关键词: CpG islands; biochemical evolution; carcinogenesis; computer assisted sequence analysis; gene frequency; neoplasm /cancer genetics; nucleic acid sequence; point mutation; pseudogenes; site directed mutagenesis; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (Adapted from the Investigator's Abstract): Most amino acid substitutions in the central domain of the p53 protein impart increased tumorigenic potential, somatic selective advantage, to the host mutant somatic cell lineage. If this tumorigenic potential varies considerably from one codon to the next, then the p53 mutational spectrum in the tumor data base will be selection driven. If the tumorigenic potential varies little from one codon to the next, then the p53 mutation spectrum in the tumor data base will be mutagenesis driven and correlated with patterns of mutagen accessibility and lesion repair rates along the p53 gene. To test the relative contributions of these two effects, we will prepare three databases, one from the tumor database (selection bias for tumorigenicity), one of base substitutions fixed during vertebrate evolution of the active p53 gene (selection bias against tumorigenicity) and one of base substitutions which were fixed in p53 pseudogenes (unbiased selection). To measure the effect of selection on the pattern of base substitutions sampled into these three p53 databases, we will apply two novel selection-sensitive analytical tools. These tools are based on properties of the genetic code and measure the average magnitude of the protein perturbation imparted by a base change. Preliminary results indicate that the codon-to-codon variations of mutation frequency in the p53 tumor database are mutagenesis driven. They also show that for mCpG->TpG transitions accumulated during vertebrate evolution, the putative the mC->G transition usually involves the C on the transcribed strand rather than the one on the nontranscribed strand because the former situation on the average effects a less drastic protein perturbation.

描述（改编自调查员的摘要）：大多数氨基酸 p53蛋白中央域中的取代增加 宿主突变体的致瘤潜力，体细胞选择性优势 体细胞谱系。 如果这种肿瘤势变化很大 从一个密码子到另一个密码子，然后是肿瘤中的p53突变谱 数据库将是选择驱动的。 如果肿瘤势变化 从一个密码子到另一个密码子，然后是p53突变频谱 肿瘤数据库将是诱变的，并与模式相关 沿p53基因的诱变剂可及性和病变修复率。 测试 这两个效果的相对贡献，我们将准备三个 数据库，一个来自肿瘤数据库的数据库（肿瘤性的选择偏见）， 活性的脊椎动物演化期间固定的基本取代之一 p53基因（针对肿瘤性的选择偏差）和碱基之一 固定在p53假基因中的取代（无偏选择）。 到 测量选择对采样基础取代模式的影响 在这三个p53数据库中，我们将应用两个新颖的选择敏感 分析工具。 这些工具基于遗传密码的属性 并测量A赋予蛋白质扰动的平均大小 基本变更。 初步结果表明密码子到棒 p53肿瘤数据库中突变频率的变化是诱变 驱动。 他们还表明，对于MCPG-> tpg转变 脊椎动物的演变，推定的MC-> G转变通常涉及 c在抄录的链上，而不是非转录链上的c 因为前者对平均效果的情况不那么剧烈的蛋白质 扰动。