The anti-apoptotic protein Mcl-1 inhibits mitochondrial Ca2+ signals

J Biol Chem. 2005 Sep 30;280(39):33637-44. doi: 10.1074/jbc.M503210200. Epub 2005 Jul 18.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Alexa 488 hydrazide
  • Aniline Compounds
  • Antibodies, Monoclonal
  • Carbocyanines
  • Fluo 4
  • Fluorescent Dyes
  • Heterocyclic Compounds, 3-Ring
  • Hydrazines
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • TO-PRO-3
  • Xanthenes
  • rhod-2