Sustained ER Ca2+ Depletion Suppresses Protein Synthesis and Induces Activation-enhanced Cell Death in Mast Cells

Depletion of Ca2+ from the endoplasmic reticulum (ER) induces large increases in cytoplasmic Ca2+, mitochondrial Ca2+ loading, protein synthesis inhibition, and cell death. To clarify the connections among these events, we have evaluated the effect of Ca2+mobilizing agents thapsigargin (Tg), econazo...

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Veröffentlicht in:The Journal of biological chemistry 2002-04, Vol.277 (16), p.13812-13820
Hauptverfasser: Soboloff, Jonathan, Berger, Stuart A.
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Sprache:eng
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Zusammenfassung:Depletion of Ca2+ from the endoplasmic reticulum (ER) induces large increases in cytoplasmic Ca2+, mitochondrial Ca2+ loading, protein synthesis inhibition, and cell death. To clarify the connections among these events, we have evaluated the effect of Ca2+mobilizing agents thapsigargin (Tg), econazole (Ec), and the growth factor Steel Factor (SLF) on bone marrow-derived mast cells (BMMCs). BMMC Ca2+ stores were found to consist of a Tg-sensitive ER compartment, the Tg-insensitive SIC store, and mitochondrial stores. Low levels of Ec interfered with Tg-stimulated mitochondrial loading while promoting progressive leakage of Ca2+ from the ER. Low levels of Ec completely reversed Tg toxicity while higher levels blocked store-operated influx and induced cell death in a SLF-enhanced manner. Both Ec and Tg inhibited protein synthesis, however, only SLF plus Tg or very high levels of Ec were able to significantly stimulate EIF-2α phosphorylation. Cycloheximide only partially protected BMMCs from Tg toxicity yet strongly synergized with Ec to induce cell death. These results therefore indicate that although both Tg and Ec deplete ER Ca2+ levels, Ec-induced cell death results from sustained protein synthesis inhibition while Tg toxicity results primarily from mitochondrial Ca2+ overload and secondarily from ER stress associated with Ca2+ depletion.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112129200