FUNCTION OF THE CPH ONCOGENE IN MAMALIAN CARCINOGENESIS

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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.