Caspase-9-induced mitochondrial disruption through cleavage of anti-apoptotic BCL-2 family members.
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.
Chen
Min
M
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030. Electronic address: minc@bcm.edu.
Guerrero
Alan D
AD
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030.
Huang
Li
L
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030.
Shabier
Zainuer
Z
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030.
Pan
Michael
M
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030.
Tan
Tse-Hua
TH
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030.
Wang
Jin
J
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030. Electronic address: jinwang@bcm.edu.
D017209:Apoptosis; D053453:Caspase 9 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D005799:Genes, Dominant; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D051020:bcl-X Protein / Q000378:metabolism*
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D045304:Cytochromes c; D053453:Caspase 9; D020169:Caspases