Abstract
Apoptosis contributes to the regulation of cell growth and regeneration and to the development of neoplasia. Mcl-1 is an anti-apoptotic protein that is particularly important for the development of hematological and biliary malignancies, but the mechanism of action of Mcl-1 is unknown. A number of pro- and anti-apoptotic proteins exhibit their effects by modulating Ca2+ signals, so we examined the effects of Mcl-1 on components of the Ca2+ signaling pathway that are known to regulate apoptosis. Expression of Mcl-1 did not affect expression of the inositol 1,4,5-trisphosphate receptor or the size of endoplasmic reticulum Ca2+ stores. However, mitochondrial Ca2+ signals induced by either Ca2+ agonists or apoptotic stimuli were decreased in cells overexpressing Mcl-1 and increased in cells in which Mcl-1 expression was inhibited. These findings provide evidence that Mcl-1 directly inhibits Ca2+ signals within mitochondria, which may provide a novel mechanism to inhibit apoptosis and thereby promote neoplasia.
Highlights
Apoptosis can result from a range of extracellular or intracellular stimuli, which converge with activation of caspases to lead directly to cell death [1]
Mitochondria play an integral role in Ca2ϩ signaling pathways and patterns
Oxidizable substrates that energize mitochondria increase the amplitude of Ca2ϩ signals and the speed of Ca2ϩ waves in the cytosol, whereas inhibitors of oxidation such as mitochondrial uncouplers dampen cytosolic Ca2ϩ signals [32]
Summary
Apoptosis can result from a range of extracellular or intracellular stimuli, which converge with activation of caspases to lead directly to cell death [1]. Mcl-1 fluorescence in the DsRed control group was Ϯ 12% of the fluorescence in non-transfected cells in co-culture, whereas fluorescence staining of InsP3R-3 was Ϯ 11%. To determine whether Mcl-1 influences ER Ca2ϩ stores, Mz-ChA-1 cells were loaded with the low affinity Ca2ϩ dye mag-fluo-4 (Kd 22 M) and examined by confocal microscopy [22].
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