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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Aniline Compounds
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Antibodies, Monoclonal / metabolism
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Apoptosis*
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Bile Duct Neoplasms / genetics
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Bile Duct Neoplasms / pathology
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Calcium Signaling / physiology*
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Carbocyanines / metabolism
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Cell Line
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Fluorescent Antibody Technique, Indirect
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Fluorescent Dyes
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Heterocyclic Compounds, 3-Ring
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Humans
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Hydrazines
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Immunohistochemistry
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Microscopy, Confocal
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Mitochondria / metabolism*
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Models, Biological
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Signal Transduction*
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Tissue Distribution
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Xanthenes
Substances
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Alexa 488 hydrazide
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Aniline Compounds
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Antibodies, Monoclonal
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Carbocyanines
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Fluo 4
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Fluorescent Dyes
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Heterocyclic Compounds, 3-Ring
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Hydrazines
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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TO-PRO-3
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Xanthenes
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rhod-2