TUMORIGENICITY OF DIFFERENT P53 MISSENSE MUTATIONS

不同 P53 错义突变的致瘤性

• 批准号: 2871994
• 负责人: GERALD P HOLMQUIST
• 金额: $ 11.17万
• 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/2871994
• 关键词: CpG islands; biochemical evolution; carcinogenesis; computer assisted sequence analysis; gene frequency; neoplasm /cancer genetics; nucleic acid sequence; p53 gene /protein; 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（改编自研究者摘要）：大多数氨基酸 在p53蛋白的中心结构域中的取代赋予增加的 致瘤潜力，体细胞选择优势，宿主突变体 体细胞谱系 如果这种致瘤潜力 从一个密码子到下一个密码子，然后肿瘤中的p53突变谱 数据库将选择驱动。 如果肿瘤发生的可能性 从一个密码子到下一个密码子的突变很少，那么p53突变谱在 肿瘤数据库将是诱变驱动的，并与 沿着p53基因的诱变剂可及性和损伤修复率。 测试 这两种效应的相对贡献，我们将准备三个 数据库，一个来自肿瘤数据库（致瘤性的选择偏倚）， 在脊椎动物进化过程中固定的一种碱基替换， p53基因（对致瘤性的选择偏好）和一个碱基 在p53假基因中固定的取代（无偏选择）。 到 测量选择对取样的碱基替换模式的影响 在这三个p53数据库中，我们将应用两个新的选择敏感的 分析工具。 这些工具是基于遗传密码的特性 并测量由蛋白质扰动引起的蛋白质扰动的平均幅度， 基地变化 初步结果表明， p53肿瘤数据库中突变频率的变化是诱变 有动力。 他们还表明，对于mCpG->TpG转换， 在脊椎动物进化中，假定的mC->G转换通常涉及 而不是在非转录链上 因为前一种情况对蛋白质的平均影响较小， 扰动