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Science 315 (5813): 856-859

Copyright © 2007 by the American Association for the Advancement of Science

Apoptosis Initiated When BH3 Ligands Engage Multiple Bcl-2 Homologs, Not Bax or Bak

Simon N. Willis,1 Jamie I. Fletcher,1 Thomas Kaufmann,1 Mark F. van Delft,1,2 Lin Chen,1 Peter E. Czabotar,1 Helen Ierino,1 Erinna F. Lee,1,2 W. Douglas Fairlie,1 Philippe Bouillet,1 Andreas Strasser,1 Ruth M. Kluck,1 Jerry M. Adams,1* David C. S. Huang1*{dagger}

Abstract: A central issue in the regulation of apoptosis by the Bcl-2 family is whether its BH3-only members initiate apoptosis by directly binding to the essential cell-death mediators Bax and Bak, or whether they can act indirectly, by engaging their pro-survival Bcl-2–like relatives. Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak.

1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
2 Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: huang_d{at}wehi.edu.au

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