REGULATION OF DNA METHYLATION BY THE RAS SIGNALING PATHWAY

We demonstrate that DNA methylation in an adrenocortical tumor cell li ne, Y1, is controlled by the Ras signaling pathway. Forced expression of a cDNA encoding human GAP(120) (hGAP), a down-modulator of Ras acti vity or partial derivative 9-Jun a transdominant negative mutant of Ju n, in Y1 cells reverts the transformed morphology of the cells and res ults in a reduction in the level of DNA methylation, DNA methyltransfe rase (MeTase) mRNA, and enzymatic activity, Introduction of an oncogen ic Ha-ras into the GAP transfectants results in reversion to a transfo rmed morphology and an increase in the levels of DNA methylation and D NA MeTase activity. Transient transfection CAT assays demonstrate that the expression of DNA MeTase promoter in Y1 cells is regulated by Ras and AP-1. These results establish a molecular link between a major si gnaling pathway involved in tumorigenesis and DNA methylation.