Calcium Induces Cell Survival and Proliferation through the Activation of the MAPK Pathway in a Human Hormone-dependent Leukemia Cell Line, TF-1

• Published in: The Journal of biological chemistry 2003-03, Vol.278 (11), p.9235-9243
• Main Authors: Apati, A, Janossy, J, Brozik, A, Imre, P B, Magocsi, M
• Format: Article
• Language: English
• Subjects: Antigens, CD34 - biosynthesis; Apoptosis; Blotting, Western; Calcium - metabolism; Caspase 3; Caspases - metabolism; Cell Cycle; Cell Death; Cell Division; Cell Nucleus - metabolism; Cell Survival; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Humans; Ionomycin - pharmacology; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Time Factors; Transcription Factor AP-1 - metabolism; Transcription, Genetic; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M205528200

Survival and proliferation of cells of a human myelo-erythroid 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 [Ca 2+ ] i induces hormone-independent survival and proliferation of TF-1 cells. We found that moderate elevation of [Ca 2+ ] i by the addition of cyclopiasonic-acid protected TF1 cells from apoptosis. Furthermore, a higher, but transient elevation of [Ca 2+ ] i by ionomycin treatment induced cell proliferation. In both cases caspase-3 activity was reduced, and Bcl-2 was up-regulated. Higher elevation of [Ca 2+ ] 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 [Ca 2+ ] 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 [Ca 2+ ] 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 [Ca 2+ ] i may influence the cytokine dependence of hemopoietic progenitors and may contribute to pathological hematopoiesis.