Epidermal growth factor‐stimulated DNA synthesis requires an influx of extracellular calcium

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Abstract
The dependency of normal cell proliferation on adequate extracellular Ca2+ levels was further investigated by determining the role of Ca2+ influx in epidermal growth factor (EGF)‐induced rat liver epithelial (T51B) cell DNA synthesis. Fura‐2‐loaded T51B cells responded with an increase in [Ca2+]i to EGF (5–50 ng/ml) that was blocked by low (25 μM) extracellular Ca2+ or by pretreatment with 50 μM La3+ to inhibit plasma membrane Ca2+ flux. Confluent T51B cells treated for 24 h with EGF (0.1–50 ng/ml) dose‐dependently incorporated [3H]‐thymidine into cell nuclei. Low extracellular Ca2+ or addition of La3+ prevented the EGF stimulated rise in labeled nuclei, indicating that a movement of Ca2+ into the cell was required for DNA synthesis. This was supported by our findings that bradykinin, which induced a rise in [Ca2+]i by opening plasma membrane Ca2+ channels in T51B cells (but not A23187, thrombin or ATP, which raise [Ca2+]i primary through mobilization of intracellular Ca2+ stores), potentiated DNA synthesis stimulated by submaximal doses of EGF. Potentiation of the action of EGF by the tumor promoter 12‐0‐tctradecanoyl‐phorbol‐13‐acetatc (TPA), indicates that activation of protein kinase C and an influx of Ca2+ share a common mechanism for initiating DNA synthesis.

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