Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis

Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
D.O.I.
10.1093/emboj/17.14.3878
Publisher site
See Article on Publisher Site

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.

Journal

The EMBO JournalWiley

Published: Jul 15, 1998

References

  • New members of the Bcl‐2 family and their protein partners
    Farrow, Farrow; Brown, Brown
  • Proximity and orientation underlie signaling by the non‐receptor tyrosine kinase ZAP70
    Graef, Graef; Holsinger, Holsinger; Diver, Diver; Schreiber, Schreiber; Crabtree, Crabtree
  • Inhibition of Ced‐3/ICE‐related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl‐2 homologue Bak
    McCarthy, McCarthy; Whyte, Whyte; Gilbert, Gilbert; Evan, Evan
  • Movement of Bax from cytosol to mitochondria during apoptosis
    Wolter, Wolter; Hsu, Hsu; Smith, Smith; Nechushtan, Nechushtan; Xi, Xi; Youle, Youle

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