It is the long term goal of these experiments to define, eventually at the molecular level, the mechanisms by which malignant transformation is induced and the mechanisms by which it is suppressed. Direct induction of transformation in hamster cells by methylating agents which are carcinogenic but not mutagenic will be measured and correlated with alterations in cellular DNA methylation levels and with tumorigenicity to determine if methylation-associated changes in gene regulation can be responsible for carcinogenesis. Cell fusions will be performed among hamster cells and between hamster and human cells which have been treated to induce tetraploidy in order to determine if the suppression of neoplastic transformation observed in fusions between normal and transformed diploid cells can be overcome by increased dosage of transformed cell chromosomes. DNA from tumor cell lines will be transfected into an unusual BHK hamster cell line which is unable to suppress transformation in order to attempt to detect and identify human oncogenes which are distinct from those isolated to date from human cells either in the way in which they are regulated or in their primary sequence. A dominant selective marker will be introduced to normal human chromosome #1 and used as a marker in cell fusions designed to test whether or not this human chromosome can suppress the malignancy of human tumor cell lines.
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