Calcium induces cell survival and proliferation through the activation of the MAPK pathway in a human hormone-dependent leukemia cell line, TF-1

Survival and proliferation of cells of a human myeloerythroid CD34+ leukemia cell line (TF-1) depend on the presence of granulocyte-macrophage colony-stimulating factor or interleukin-3. Upon hormone withdrawal these cells stop proliferating and undergo apoptotic process. In this report we demonstrate that a controlled increase in [Ca2+](i) induces hormone-independent survival and proliferation of TF-1 cells. We found that moderate elevation of [Ca2+](i) by the addition of cyclopiasonic-acid protected TF1 cells from apoptosis. Furthermore, a higher, but transient elevation of [Ca2+](i) by ionomycin treatment induced cell proliferation. In both cases caspase-3 activity was reduced, and Bcl-2 was upregulated. Higher elevation of [Ca2+](i) by ionomycin induced MEK-dependent biphasic ERK1/2 activation, sufficient to move the cells from G(0)/G(1) to S/M phases. Meanwhile, activation of ERK1/2, phosphorylation of the Elk-1 transcription factor, and, consequently, a substantial elevation of Egr-1 and c-Fos levels and AP-1 DNA binding were observed. Moderate elevation of [Ca2+](i), on the other hand, caused a delayed monophasic activation of ERK1/2 and Elk-1 that was accompanied with only a small increase of Egr-1 and c-Fos levels and AP-1 DNA binding. The specific MEK-1 kinase inhibitor, PD98059, inhibited all the effects of increasing [Ca2+](i), indicating that the MAPK/ERK pathway activation is essential for TF-1 cell survival and proliferation. Based on these results we suggest that the elevation of the [Ca2+](i) may influence the cytokine dependence of hemopoietic progenitors and may contribute to pathological hematopoiesis.