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Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis
- Source :
- The EMBO journal. 17(14)
- Publication Year :
- 1998
-
Abstract
- Expression of the pro-apoptotic molecule BAX has been shown to induce cell death. While BAX forms both homo- and heterodimers, questions remain concerning its native conformation in vivo and which moiety is functionally active. Here we demonstrate that a physiologic death stimulus, the withdrawal of interleukin-3 (IL-3), resulted in the translocation of monomeric BAX from the cytosol to the mitochondria where it could be cross-linked as a BAX homodimer. In contrast, cells protected by BCL-2 demonstrated a block in this process in that BAX did not redistribute or homodimerize in response to a death signal. To test the functional consequence of BAX dimerization, we expressed a chimeric FKBP-BAX molecule. Enforced dimerization of FKBP-BAX by the bivalent ligand FK1012 resulted in its translocation to mitochondria and induced apoptosis. Caspases were activated yet caspase inhibitors did not block death; cytochrome c was not released detectably despite the induction of mitochondrial dysfunction. Moreover, enforced dimerization of BAX overrode the protection by BCL-XL and IL-3 to kill cells. These data support a model in which a death signal results in the activation of BAX. This conformational change in BAX manifests in its translocation, mitochondrial membrane insertion and homodimerization, and a program of mitochondrial dysfunction that results in cell death.
- Subjects :
- Programmed cell death
Recombinant Fusion Proteins
bcl-X Protein
Caspase 3
Apoptosis
Mitochondrion
Cysteine Proteinase Inhibitors
Ligands
General Biochemistry, Genetics and Molecular Biology
Tacrolimus
Amino Acid Chloromethyl Ketones
Cell Line
Membrane Potentials
Mice
Bcl-2-associated X protein
Cytosol
Proto-Oncogene Proteins
Animals
Humans
Inner mitochondrial membrane
Molecular Biology
Caspase
bcl-2-Associated X Protein
General Immunology and Microbiology
biology
General Neuroscience
Cytochrome c
Molecular biology
Caspase 9
Cell biology
Mitochondria
Rats
Enzyme Activation
Cysteine Endopeptidases
Proto-Oncogene Proteins c-bcl-2
Caspases
biology.protein
Interleukin-3
Dimerization
Research Article
Subjects
Details
- ISSN :
- 02614189
- Volume :
- 17
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- The EMBO journal
- Accession number :
- edsair.doi.dedup.....a64d8a3a1788f117765294f213f8a375