EXPRESSION OF THE HUMAN C-K-RAS GENE

描述：(改编自申请者摘要)： 研究人员对体细胞突变激活的作用的研究 C-K-ras基因在人类结直肠肿瘤发生发展中的作用 C-K-ras基因突变的分子性质差异 基因座与发育差异显著相关， 癌症的进展阶段和发病时间。更具体地说，天冬氨酸 C-K-ras基因第13密码子的酸替换(ASP13突变)是 主要见于老年患者的腺瘤和癌 与含有其他c-K-ras突变或不含c-K-ras突变的肿瘤相比 RAS突变。研究人员的工作假说假定 ASP13诱导c-K-ras基因产物的结构变化 突变赋予蛋白质相对较弱的致癌活性 其他激活突变，特别是密码子上的天冬氨酸突变 12(ASP12突变)。这种亚微观差异奠定了一种 导致最终宏观差异的多效性事件链 这可能与出现症状的延迟5-10年一样明显 肿瘤。这项提案的主要目标将是分析分子 C-K-ras ASP13基因在结直肠癌晚期发病的基础 突变，通过测试一些预测，调查人员 假设是假定的。调查人员将进行一项比较 分析：1)致癌基因损伤的相对程度 有和没有这种突变的结直肠肿瘤；2)生物学的(2a) 和c-K-ras p21与ASP13的生化(2b)性质 C-K-ras基因的相对致癌外显率 与体内的这种和其他突变；以及4)相对可及性或 C-K-ras密码子13与密码子12对致癌物敏感性的体外比较 (4a)和体内(4b)。调查人员的研究应该定义 致癌基因内在差异的分子机制 在所有ras突变中，asp12和asp12是最主要的突变 ASP13突变，并直接关系到该问题的启动作用 最常见于自发性的ras癌基因的致癌作用 和致癌物诱导的肿瘤，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.