EXPRESSION OF AN EXOGENOUS EUKARYOTIC DNA METHYLTRANSFERASE GENE INDUCES TRANSFORMATION OF NIH-3T3 CELLS

Abnormal regional increases in DNA methylation, which have potential f or causing gene inactivation and chromosomal instability, are consiste ntly found in immortalized and tumorigenic cells. Increased DNA methyl transferase activity, which is also a characteristic of such cells, is a candidate to mediate these abnormal DNA methylation patterns. We no w show that, in NIH 3T3 mouse fibroblasts, constitutive overexpression of an exogenous mouse DNA methyltransferase gene results in a marked increase in overall DNA methylation which is accompanied by tumorigeni c transformation. These transformation changes can also be elicited by dexamethasone-inducible expression of an exogenous DNA methyltransfer ase gene. Our findings provide strong evidence that the increase in DN A methyltransferase activity associated with tumor progression could b e a key step in carcinogenesis and provide a model system that can be used to further study this possibility.