FUNCTION OF THE CPH ONCOGENE IN MAMALIAN CARCINOGENESIS

产品说明： 肿瘤的发展是由于 在暴露的细胞中积累遗传和表观遗传改变 致癌的侮辱。 癌基因激活和肿瘤丢失 抑制因子是驱动正常细胞向肿瘤细胞转化的中心事件。 状态 对癌基因的检测和分离提供了 在分子水平上研究它们在发病和.或 肿瘤的发展。 因为大多数人类疾病的未知病因 癌症和人类细胞对肿瘤的内在抵抗力 在体外转化中，PI一直致力于分子分析， 叙利亚仓鼠胎儿细胞转化系统，作为替代模型 对于非常接近人类情况的体外致癌作用（November 例如， Oncogene 5：1425-1430，1990）。 由于这项工作， 已经克隆了称为cph的新癌基因（Velasco等， Oncogene 9：2065-2069，1994）从仓鼠肿瘤细胞中诱导 3-甲基胆蒽（3 MC）。 与以下基因组序列同源的基因组序列： 仓鼠CPH癌基因已经从酵母到人类细胞中被检测到 这表明它起着重要的非细胞作用。 各种CPH- 在正常和转化细胞中检测到相关的mRNA种类 仓鼠胚胎细胞 cph癌基因能够转化 NIH/3 T3细胞。 此外，cph与 ras癌基因：a）它与H-ras在肿瘤细胞中协同作用， 转化NIH/3 T3细胞，B）其表达在NIH/3 T3细胞中开启， 在用N-ras癌基因转染后的鼠成纤维细胞，和c） 从转化的大肠杆菌中克隆到的cph全长cDNA的序列分析 细胞将cph蛋白鉴定为假定的ras GDP交换器 蛋白 该建议的重点是分子分析， 仓鼠cph癌基因，重点放在以下方面：（目的I） 确定cph原激活的机制， 癌基因，（Aim II）cph癌基因参与ras 啮齿动物细胞的肿瘤转化的转化途径， 和（目的III）表征其对 仓鼠肿瘤细胞和cph转化细胞的恶性状态 鼠成纤维细胞。 实验的目的是了解 cph原癌基因的基本分子途径 参与和细胞的变化，通过它有助于 肿瘤的发展。 这些研究将扩大我们对 癌基因在癌症中的作用，并提供更多的见解， 在致癌过程中的步骤。 长期目标是 建议是扩大知识获得的仓鼠cph 癌基因对人体细胞，并应用它来研究可能的作用 在人类肿瘤中的作用。

DESCRIPTION: Tumor development results from the sequential accumulation of genetic and epigenetic alterations in cells exposed to carcinogenic insult. Oncogene activation and loss of tumor suppressor are central events driving normal cells to the neoplastic state. Detection and isolation on oncogenes provide the means to investigate at the molecular level their role in the onset and.or development of neoplasia. Because the unknown etiology of most human cancers and the intrinsic resistance of human cells to neoplastic conversion in vitro, the PI has worked on the molecular analysis of the Syrian hamster fetal cell transformation system, as an alternative model for in vitro carcinogenesis very close to the human situation (Notario et al., Oncogene 5: 1425-1430, 1990). As a result of this work a novel oncogene, termed cph, has been cloned (Velasco et al., Oncogene 9:2065-2069, 1994) from hamster neoplastic cells initiated with 3-methylcholanthrene (3MC). Genomic sequences with homology to the hamster cph oncogene have been detected from yeast to human cells suggesting that it plays an important acellular role. Various cph- related mRNA species have been detected in normal and transformed hamster embryo cells. The cph oncogene is able to transform NIH/3T3 cells. In addition, cph shares functional pathways with ras oncogenes: a) it acts synergistically with H-ras in the transformation of NIH/3T3 cells, b) its expression is turned on in murine fibroblasts upon transfection with the N-ras oncogene, and c) sequence analysis of a full-length cph cDNA cloned from transformed cells identifies the cph protein as a putative ras GDP-exchanger protein. This proposal focuses on the molecular analysis of the hamster cph oncogene with emphasis on the following areas: (Aim I) identification of the mechanism of activation of the cph proto- oncogene, (Aim II) participation of the cph oncogene in ras transformation pathways for the neoplastic conversion of rodent cells, and (Aim III) characterization of its phenotypic contribution to the malignant state of hamster neoplastic cells and of cph-transformed murine fibroblasts. The experimentation is designed to understand the basic molecular pathways in which the cph proto-oncogene participates and the cellular alterations through which it contributes to tumor development. These studies will expand our knowledge on the role of oncogenes in cancer and provide additional insights into the steps in the carcinogenesis process. The long term goal of this proposal is to extend the knowledge gained on the hamster cph oncogene to human cells, and to apply it to study the possible role of cph in human neoplasia.