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Apoptosis Initiated When BH3 Ligands Engage Multiple Bcl-2 Homologs, Not Bax or Bak
Simon N. Willis,1Jamie I. Fletcher,1Thomas Kaufmann,1Mark F. van Delft,1,2Lin Chen,1Peter E. Czabotar,1Helen Ierino,1Erinna F. Lee,1,2W. Douglas Fairlie,1Philippe Bouillet,1Andreas Strasser,1Ruth M. Kluck,1Jerry M. Adams,1*David C. S. Huang1*
A central issue in the regulation of apoptosis by the Bcl-2family is whether its BH3-only members initiate apoptosis bydirectly binding to the essential cell-death mediators Bax andBak, or whether they can act indirectly, by engaging their pro-survivalBcl-2–like relatives. Contrary to the direct-activationmodel, we show that Bax and Bak can mediate apoptosis withoutdiscernable association with the putative BH3-only activators(Bim, Bid, and Puma), even in cells with no Bim or Bid and reducedPuma. Our results indicate that BH3-only proteins induce apoptosisat least primarily by engaging the multiple pro-survival relativesguarding 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.
To whom correspondence should be addressed. E-mail: huang_d{at}wehi.edu.au
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