Ion Transport in the Regulation of Cell Proliferation in ras Oncogene Expressing 3T3 NIH Fibroblasts

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Abstract
The expression of ras oncogene in NIH 3T3 fibroblasts is followed by profound alterations of ion transport across the cell membrane. On the one hand, ras-oncogene-expressing cells -unlike normal cells – respond to bradykinin, bombesin and serum with sustained oscillations of cell membrane potential, due to oscillations of intracellular calcium activity and subsequent activation of calcium-sensitive K+ channels. These oscillations depend on the hormone-stimulated entry of calcium from the extracellular space but at least partially involve calcium release from intracellular stores. On the other hand, the expression of the ras oncogene leads to a marked shift of the set point for volume-regulatory ion transport with subsequent activation of the Na+/H+ exchanger and the Na+, K+,2C1- cotransport, both carriers serving the regulatory cell volume increase. As a result, ras-oncogene-expressing cells are larger and more alkaline than cells that do not express the ras oncogene. The growth-factor-independent proliferation of ras-oncogene-expressing cells is abolished following inhibition of the Na+/K+,2Cl- cotransporter (by furosemide), inhibition of the Na+/H+ exchanger (by dimethylamiloride) and inhibition of bradykinin-induced calcium entry (by nifedipine). Thus, activation of the volume-regulatory ion transporters and the agonist-induced oscillations of intracellular calcium activity are apparently prerequisites for the growth-factor-independent proliferation of ras-oncogene-expressing cells.

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