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.
The EMBO Journal – Wiley
Published: Jul 15, 1998
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