The effect of Val12 Ha-ras on the transplasma membrane electron transport system of C3H 10T1/2 mouse fibroblasts

The transplasma membrane electron transport system and some oncogenes have been demonstrated to play a role in the control of cell functions and cell growth. I have studied the effect of oncogenic Ha-ras on transplasma membrane electron transport of C3H 10T1/2 mouse fibroblasts. I have discovered that unlike SV40 transformation (in rat or mouse cell lines), transfection of C3H 10T1/2 cells with activated ras causes an increase in redox activity. An additional aspect of ras, which is not seen in the normal cells, is the production of superoxide. The increase in the activity of the cells transfected with activated Ha-ras is partially due to increased reduced pyridine nucleotides and the production of superoxide. Growth factors such as insulin and epidermal growth factor, which have been demonstrated by others to be upstream of ras in the intercellular signaling cascade, increase the rate of ferricyanide reduction of the normal but not the ras-transfected cells thus providing additional evidence for ras control of transplasma membrane electron transport. Reduction of external oxidants is correlated with the release of protons, again demonstrating an increase in activity in the presence of activated Ha-ras. The growth of the cells transfected with activated ras (but not the normal cells) can be stimulated, to a limited extent, by traditional growth factors and oxidants. I have concluded that ras is involved with, and exerts a controlling influence on the transplasma membrane electron transport system. Lastly, I have discovered that the presence of activated ras decreases the cytotoxic effects of the antitumor drug adriamycin in agreement with less inhibition of the ferricyanide reductase activity of the cells. Another antitumor drug, cisplatin, which does not block redox activity, is not as effective in killing these cells. The finding that different transforming genes have different effects on the transplasma membrane electron transport activity, and the fact that the effectiveness of an antitumor drug parallels the effectiveness of the drug in blocking redox activity indicates that assaying transplasma membrane electron transport activity may determine which drug is best for a particular cancer therapy