Two types of genes that participate directly in the development of malignancy ,ave been identified so far. Oncogenes are activated in tumor cells where they produce proteins whose function contributes to the malignant phenotype. In contrast, cancer suppressor genes are active in non-malignant cells where they apparently act to ensure normal growth and development, and their function is lost as cells become malignant. Experiments are proposed in this grant to make use of a line of tumorigenic hamster fibroblasts whose transformed phenotype is able to be suppressed by normal human fibroblasts in order to (1) clone the gene in the normal human genome able to control hamster cell transformation and then to test its ability to block the in vitro transformation and in vivo tumorigenicity of human tumor cell lines. (2) insert a dominant selectable genetic marker into the chromosome of the normal human fibroblast that is able to control hamster cell transformation (and on other chromosomes associated by cytogenetic data with tumor suppression) then to transfer the tagged chromosome singly to human tumor lines and test its efficacy in controlling transformation and tumorigenicity. To test the hypothesis that cancer suppressor genes act to block the activity and/or function of tumor oncogenes, hamster cells and hamster-human hybrids that either express or do not express the ability to suppress transformation will be tested for their susceptibility to and ability to regulate a subset of oncogenes.
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