The anti-apoptotic protein Mcl-1 inhibits mitochondrial Ca2+ signals.
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.
Minagawa
Noritaka
N
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8019, USA.
Kruglov
Emma A
EA
Dranoff
Jonathan A
JA
Robert
Marie E
ME
Gores
Gregory J
GJ
Nathanson
Michael H
MH
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000814:Aniline Compounds; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000473:pathology; D020013:Calcium Signaling / Q000502:physiology*; D002232:Carbocyanines / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D006834:Hydrazines; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution; D014966:Xanthenes
C417561:Alexa 488 hydrazide; D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D002232:Carbocyanines; C409648:Fluo 4; D005456:Fluorescent Dyes; D006575:Heterocyclic Compounds, 3-Ring; D006834:Hydrazines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C098830:TO-PRO-3; D014966:Xanthenes; C068483:rhod-2