Caspase-9-induced mitochondrial disruption through cleavage of anti-apoptotic BCL-2 family members

Min Chen, Alan D Guerrero, Li Huang, Zainuer Shabier, Michael Pan, Tse-Hua Tan, Jin Wang

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Mitochondrial disruption during apoptosis results in the release of cytochrome c that forms apoptosomes with Apaf-1 and caspase-9. Activation of caspase-9 by dimerization in apoptosomes then triggers a caspase signaling cascade. In addition, other apoptosis signaling molecules released from the mitochondrion, such as apoptosis-inducing factor and endonuclease G, may induce caspase-9-independent apoptosis. To determine the signaling events induced by caspase-9, we used chemically induced dimerization for specific activation of caspase-9. We observed that caspase-9 dimerization resulted in the loss of mitochondrial membrane potential and the cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1. Moreover, cleavage-resistant Bcl-2, Bcl-xL, or Mcl-1 potently inhibited caspase-9-dependent loss of mitochondrial membrane potential and the release of cytochrome c. Our data suggest that a caspase-9 signaling cascade induces feedback disruption of the mitochondrion through cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1.

Original languageEnglish (US)
Pages (from-to)33888-95
Number of pages8
JournalThe Journal of biological chemistry
Volume282
Issue number46
DOIs
StatePublished - Nov 16 2007

Keywords

  • Apoptosis
  • Caspase 9
  • Caspases
  • Cytochromes c
  • Dimerization
  • Enzyme Activation
  • Genes, Dominant
  • Humans
  • Jurkat Cells
  • Mitochondria
  • Models, Biological
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2
  • Signal Transduction
  • bcl-X Protein
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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