Response of FR3T3 cells transformed by HA‐ras oncogene and epidermal growth factor gene to differentiation induction by N,N‐dimethylformamide

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Abstract
Treatment of chemically transformed fibroblasts with N,N‐dimethylformamide (DMF) results in the restoration of a non‐transformed phenotype. In an attempt to identify more precisely the mechanisms by which DMF reverses the transformed phenotype, the effects of DMF on fibroblasts which were transformed by a single gene—specifically a synthetic epidermal growth factor (EGF) gene or the Ha‐ras oncogene—were examined. The constitutive expression of either the Ha‐ras oncogene or the EGF gene in FR3T3 fibroblasts resulted in cellular transformation. The effect of the differentiation‐inducing agent DMF on several properties of these transformed cell lines was examined. The EGF‐transfected cells were much more responsive to DMF than the ras‐transfected cells. DMF treatment of the EGF‐transfected cells resulted in the inhibition of anchorage‐independent growth, the restoration of a normal cellular morphology and growth rate in monolayer culture, and the down‐regulation of the proliferation‐associated nucleolar protein B23. DMF treatment had a much slighter effect on growth of the ras‐transfected cells in monolayer culture or under anchorage‐independent growth conditions. The high proliferation rate of the ras‐3 cells was associated with elevated expression of protein B23. The 19‐3 cells, but not the ras‐3 cells, expressed cell‐surface fibronectin. Treatment of the ras‐3 cells with DMF did not restore fibronectin expression. The binding of EGF was increased 3‐fold in the EGF‐transfected cells and decreased 20‐fold in ras‐transfected cells, but in neither case did DMF alter EGF binding. DMF treatment increased the secretion of EGF in the 2 transfected lines as well as in control cells. These results suggest that the aberrant‐growth control in the EGF‐transfected cells, but not in the ras‐transfected cells, could be modulated by DMF and that the aberrant‐growth control mechanisms were different in these 2 cell types.