to-pro-3 and Bile-Duct-Neoplasms

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.

Topics: Adenocarcinoma; Aniline Compounds; Antibodies, Monoclonal; Apoptosis; Bile Duct Neoplasms; Calcium Signaling; Carbocyanines; Cell Line; Cell Line, Tumor; Cell Nucleus; Fluorescent Antibody Technique, Indirect; Fluorescent Dyes; Heterocyclic Compounds, 3-Ring; Humans; Hydrazines; Immunohistochemistry; Microscopy, Confocal; Mitochondria; Models, Biological; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tissue Distribution; Xanthenes