Phorbol 12-myristate 13-acetate, ionomycin or ouabain, and raised extracellular magnesium induce proliferation of chicken heart mesenchymal cells.

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Abstract
Cultured chicken heart mesenchymal cells are proliferatively quiescent at low densities in medium containing plasma at 10%. Mitogenic hormones like epidermal growth factor and insulin-like growth factors cause these cells to proliferate very actively, as does infection with avian sarcoma viruses, erythroblastosis virus, or myelocytomatosis virus. The combination of phorbol 12-myristate 13-acetate (PMA), ionomycin or ouabain and raised extracellular Mg, likewise, causes these cells to proliferate very actively. Although these agents have no significant effect when acting singly, the combination of PMA at 100 ng/ml and 0.5 .mu.M ionomycin induces a 6-fold increase in cell number at 4 days, and the combination of PMA, ionomycin, and 5.6 mM Mg induces 12-fold multiplication. PMA plus 1 .mu.M ouabain induces 3-fold multiplication, whereas the combination of PMA, ouabain and Mg induces 6-fold multiplication. The tumor promoter PMA, like diacylglycerol released by breakdown of plasma membrane phosphatidylinositol diphosphate, is known to activate the serine- and threonine-specific intracellular enzyme kinase C. The divalent cation ionophore ionomycin is known to carry calcium into cells down an electrochemical gradient, and the Na+, K+-ATPase inhibitor ouabain appears to elevate intracellular Ca by means of a Na-mediated exchange mechanism. Mg, like Ca is known to enter cells passively down an electrochemical gradient and to be involved in the regulation of many key intracellular reactions. Findings with PMA, ionotropes and Mg support a hypothesis that diacylglycerol-mediated activation of kinase C plus cellular divalent cation influx and/or mobilization, caused by the action of mitogenic hormones or the protein products of onc genes, are key events in the initiation of cell replication.

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