EXPRESSION OF THE HUMAN C-K-RAS GENE

描述：（改编自申请人摘要）：在 研究人员对体细胞突变激活的作用的研究， c-K-ras基因在人类结肠直肠肿瘤发生中的作用，他们发现， c-K-ras基因突变的分子性质差异 位点与发育差异显著相关， 进展阶段和癌症发作时间。 更具体地说，天冬氨酸 c-K-ras基因密码子13处的酸取代（ASP 13突变）是 主要见于老年患者的腺瘤和癌 与那些含有其他c-K-ras突变的肿瘤或没有 ras突变。 研究人员的工作假设假定， ASP 13诱导的c-K-ras基因产物的结构变化 突变赋予蛋白质较弱的致癌活性， 其他激活突变，特别是密码子处的天冬氨酸突变 12（ASP12突变）。 这种亚微观的差异是 导致最终宏观差异的多效性事件链 这可能是一样明显的延迟5 - 10年的发病症状 肿瘤形成 这项提案的主要目标是分析分子 c-K-ras ASP 13在大肠癌迟发性中的作用 突变，通过测试一些预测，研究人员 假设假设 调查人员将进行比较 分析：1）致癌遗传损伤的相对程度， 有和没有这种突变的结肠直肠肿瘤; 2）生物学（2a） 和生化（2b）特性的c-K-ras p21与ASP 13相比， 3）c-K-ras基因的相对致癌率 与这种和其他突变在体内;和4）相对可及性或 c-K-ras基因13和12密码子对致癌物的敏感性 (4a)体内（4b）。 研究者的研究应定义 致癌基因的内在差异的分子机制 所有ras突变中最主要的突变，ASP 12和 ASP13突变，并直接承担问题的启动作用 ras癌基因的致癌作用最常见于自发性 以及致癌物诱发的肿瘤c-K-ras。

DESCRIPTION: (Adapted from applicant's abstract): During the investigators's studies on the role of somatic mutational activation of the c-K-ras gene in human colo-rectal tumorigenesis, they have found that differences in the molecular nature of mutations occurring in the c-K-ras locus are significantly correlated with differences in the development, stage of progression and time of cancer onset. More specifically, aspartic acid substitutions at codon 13 (ASP13 mutations) of the c-K-ras gene are found predominantly in adenomas and in carcinomas of older patients compared with those containing other c-K-ras mutations or in tumors without ras mutations. The investigators working hypothesis postulates that the structural changes induced in the c-K-ras gene product by the ASP13 mutation confer a weaker oncogenic activity to the protein relative to other activating mutations, especially the aspartic acid mutation at codon 12 (ASP12 mutation). This submicroscopic difference underlies a pleiotropic chain of events resulting in ultimate macroscopic differences that can be as obvious as a delay of 5-10 years in the onset of symptomatic neoplasia. The main goal of this proposal will be to analyze the molecular basis for the late onset of colo-rectal carcinomas with the c-K-ras ASP13 mutation, by testing a number of predictions that the investigators hypothesis postulates. The investigators will carry out a comparative analysis of: 1) the relative extent of oncogenic genetic damage in colo-rectal tumors with and without this mutation; 2) the biological (2a) and biochemical (2b) properties of c-K-ras p21 with the ASP13 versus other mutations in vitro; 3) the relative oncogenic penetrance of c-K-ras genes with this and other mutations in vivo; and 4) the relative accessibility or sensitivity to carcinogens of c-K-ras codon 13 versus codon 12 in vitro (4a) and in vivo (4b). The investigators studies should define the molecular mechanisms underlying the intrinsic differences in the oncogenic potential of the most predominant of all the ras mutations, the ASP12 and ASP13 mutations, and bear directly on the issue of the role in initiation of carcinogenesis of the ras oncogene most commonly found in spontaneous and carcinogen-induced tumors, the c-K-ras.