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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}

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FASEB J 24, 93-104
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Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-xL, and Mcl-1.
S. Chen, Y. Dai, X.-Y. Pei, and S. Grant (2009)
Mol. Cell. Biol. 29, 6149-6169
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VDAC2 is required for truncated BID-induced mitochondrial apoptosis by recruiting BAK to the mitochondria.
S. S. Roy, A. M. Ehrlich, W. J. Craigen, and G. Hajnoczky (2009)
EMBO Rep. 10, 1341-1347
   Abstract »    Full Text »    PDF »
The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways.
M. Rahmani, A. Anderson, J. R. Habibi, T. R. Crabtree, M. Mayo, H. Harada, A. Ferreira-Gonzalez, P. Dent, and S. Grant (2009)
Blood 114, 4507-4516
   Abstract »    Full Text »    PDF »
p16INK4A Sensitizes Human Leukemia Cells to FAS- and Glucocorticoid-induced Apoptosis via Induction of BBC3/Puma and Repression of MCL1 and BCL2.
P. Obexer, J. Hagenbuchner, M. Rupp, C. Salvador, M. Holzner, M. Deutsch, V. Porto, R. Kofler, T. Unterkircher, and M. J. Ausserlechner (2009)
J. Biol. Chem. 284, 30933-30940
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Novel Bcl-2 Homology-3 Domain-like Sequences Identified from Screening Randomized Peptide Libraries for Inhibitors of the Pro-survival Bcl-2 Proteins.
E. F. Lee, A. Fedorova, K. Zobel, M. J. Boyle, H. Yang, M. A. Perugini, P. M. Colman, D. C. S. Huang, K. Deshayes, and W. D. Fairlie (2009)
J. Biol. Chem. 284, 31315-31326
   Abstract »    Full Text »    PDF »
MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts.
J. K. Brunelle, J. Ryan, D. Yecies, J. T. Opferman, and A. Letai (2009)
J. Cell Biol. 187, 429-442
   Abstract »    Full Text »    PDF »
Apoptotic Signaling Activated by Modulation of the F0F1-ATPase: Implications for Selective Killing of Autoimmune Lymphocytes.
T. B. Sundberg, L. Swenson, D. R. Wahl, A. W. Opipari Jr., and G. D. Glick (2009)
J. Pharmacol. Exp. Ther. 331, 437-444
   Abstract »    Full Text »    PDF »
Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands.
E. F. Lee, P. E. Czabotar, H. Yang, B. E. Sleebs, G. Lessene, P. M. Colman, B. J. Smith, and W. D. Fairlie (2009)
J. Biol. Chem. 284, 30508-30517
   Abstract »    Full Text »    PDF »
Activation of Tumor Suppressor Protein p53 Is Required for Theiler's Murine Encephalomyelitis Virus-Induced Apoptosis in M1-D Macrophages.
K.-N. Son, S. Pugazhenthi, and H. L. Lipton (2009)
J. Virol. 83, 10770-10777
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Identification of Novel in Vivo Phosphorylation Sites of the Human Proapoptotic Protein BAD: PORE-FORMING ACTIVITY OF BAD IS REGULATED BY PHOSPHORYLATION.
L. Polzien, A. Baljuls, U. E. E. Rennefahrt, A. Fischer, W. Schmitz, R. P. Zahedi, A. Sickmann, R. Metz, S. Albert, R. Benz, et al. (2009)
J. Biol. Chem. 284, 28004-28020
   Abstract »    Full Text »    PDF »
Toxoplasma gondii infection confers resistance against BimS-induced apoptosis by preventing the activation and mitochondrial targeting of pro-apoptotic Bax.
D. Hippe, A. Weber, L. Zhou, D. C. Chang, G. Hacker, and C. G. K. Luder (2009)
J. Cell Sci. 122, 3511-3521
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BH3-only proteins Mcl-1 and Bim as well as endonuclease G are targeted in spongistatin 1-induced apoptosis in breast cancer cells.
U. M. Schneiders, L. Schyschka, A. Rudy, and A. M. Vollmar (2009)
Mol. Cancer Ther. 8, 2914-2925
   Abstract »    Full Text »    PDF »
New Advances in the Second-Line Treatment of Small Cell Lung Cancer.
J. L. Hurwitz, F. McCoy, P. Scullin, and D. A. Fennell (2009)
Oncologist 14, 986-994
   Abstract »    Full Text »    PDF »
Vesicular Stomatitis Virus Induces Apoptosis Primarily through Bak Rather than Bax by Inactivating Mcl-1 and Bcl-XL.
A. F. Pearce and D. S. Lyles (2009)
J. Virol. 83, 9102-9112
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Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis.
G. Dewson and R. M. Kluck (2009)
J. Cell Sci. 122, 2801-2808
   Abstract »    Full Text »    PDF »
The role of BH3-only protein Bim extends beyond inhibiting Bcl-2-like prosurvival proteins.
D. Merino, M. Giam, P. D. Hughes, O. M. Siggs, K. Heger, L. A. O'Reilly, J. M. Adams, A. Strasser, E. F. Lee, W. D. Fairlie, et al. (2009)
J. Cell Biol. 186, 355-362
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The Fowlpox Virus BCL-2 Homologue, FPV039, Interacts with Activated Bax and a Discrete Subset of BH3-Only Proteins To Inhibit Apoptosis.
L. Banadyga, K. Veugelers, S. Campbell, and M. Barry (2009)
J. Virol. 83, 7085-7098
   Abstract »    Full Text »    PDF »
Context-dependent Bcl-2/Bak Interactions Regulate Lymphoid Cell Apoptosis.
H. Dai, X. W. Meng, S.-H. Lee, P. A. Schneider, and S. H. Kaufmann (2009)
J. Biol. Chem. 284, 18311-18322
   Abstract »    Full Text »    PDF »

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