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 journalArticlepeer-review

    100 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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