Journal ArticleDOI
Apoptosis Initiated When BH3 Ligands Engage Multiple Bcl-2 Homologs, Not Bax or Bak
Simon N. Willis,Jamie I. Fletcher,Thomas Kaufmann,Mark F. van Delft,Mark F. van Delft,Lin Chen,Peter E. Czabotar,Helen Ierino,Erinna F. Lee,Erinna F. Lee,W. Douglas Fairlie,Philippe Bouillet,Andreas Strasser,Ruth M. Kluck,Jerry M. Adams,David C.S. Huang +15 more
TLDR
Contrary to the direct-activation model, it is shown that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma).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.read more
Citations
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Journal ArticleDOI
The BCL-2 protein family: opposing activities that mediate cell death
TL;DR: New insights into interactions among BCL-2 family proteins reveal how these proteins are regulated, but a unifying hypothesis for the mechanisms they use to activate caspases remains elusive.
Journal ArticleDOI
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy
TL;DR: The biochemical, structural and genetic studies that have clarified how the interplay between members of the BCL-2 family on mitochondria sets the apoptotic threshold are discussed, illuminating the physiological control of apoptosis, the pathological consequences of its dysregulation and the promising search for novel cancer therapies that target the BCA2 protein family.
Journal ArticleDOI
The Bcl-2 apoptotic switch in cancer development and therapy
J. M. Adams,Suzanne Cory +1 more
TL;DR: Better understanding of the Bcl-2 family is clarifying its role in cancer development, revealing how conventional therapy works and stimulating the search for ‘BH3 mimetics’ as a novel class of anticancer drugs.
Journal ArticleDOI
The Role of Mitochondria in Apoptosis
Chunxin Wang,Richard J. Youle +1 more
TL;DR: Comparing and contrast apoptosis pathways in Caenorhabditis elegans, Drosophila melanogaster, and mammals that indicate major mysteries remaining to be solved are compared.
Journal ArticleDOI
The BCL-2 Family Reunion
TL;DR: The mechanisms and functions of the BCL-2 family are discussed in the context of these pathways, highlighting the complex integration and regulation of the b cell CLL/lymphoma-2family in cell fate decisions.
References
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An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Tilman Oltersdorf,Steven W. Elmore,Alexander R. Shoemaker,Robert C. Armstrong,David J. Augeri,Barbara A. Belli,Milan Bruncko,Thomas L. Deckwerth,Jürgen Dinges,Philip J. Hajduk,Mary K. Joseph,Shinichi Kitada,Stanley J. Korsmeyer,Stanley J. Korsmeyer,Kunzer Aaron R,Anthony Letai,Chi Li,Michael J. Mitten,David G. Nettesheim,Shi Chung Ng,Paul Nimmer,Jacqueline M. O'Connor,Anatol Oleksijew,Andrew M. Petros,John C. Reed,Wang Shen,Stephen K. Tahir,Craig B. Thompson,Kevin J. Tomaselli,Baole Wang,Wendt Michael D,Haichao Zhang,Stephen W. Fesik,Saul H. Rosenberg +33 more
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Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function
Lin Chen,Simon N. Willis,Andrew H. Wei,Brian J. Smith,Jamie I. Fletcher,Mark G. Hinds,Peter M. Colman,Catherine L. Day,Jerry M. Adams,David C.S. Huang +9 more
TL;DR: The results suggest that apoptosis relies on selective interactions between particular subsets of these proteins and that it should be feasible to discover BH3-mimetic drugs that inactivate specific prosurvival targets.
Journal ArticleDOI
BCL-2, BCL-XL Sequester BH3 Domain-Only Molecules Preventing BAX- and BAK-Mediated Mitochondrial Apoptosis
Emily H. Cheng,Michael C. Wei,Solly Weiler,Richard A. Flavell,Tak W. Mak,Tullia Lindsten,Stanley J. Korsmeyer +6 more
TL;DR: In mammals, BH3 domain-only molecules activate multidomain proapoptotic members to trigger a mitochondrial pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction.
Journal ArticleDOI
Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.
Anthony Letai,Michael C. Bassik,Loren D. Walensky,Mia D. Sorcinelli,Solly Weiler,Stanley J. Korsmeyer +5 more
TL;DR: A two-class model for BH3 domains is supported: BID-like domains that "activate" BAX, BAK and BAD-like domain that "sensitize" by occupying the pocket of antiapoptotic members.
Journal ArticleDOI
Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.
Philippe Bouillet,Donald Metcalf,David C.S. Huang,David M. Tarlinton,Thomas W.H. Kay,Frank Köntgen,Jerry M. Adams,Andreas Strasser +7 more
TL;DR: Gene targeting in mice revealed important physiological roles for Bim and revealed that Bim is required for hematopoietic homeostasis and as a barrier to autoimmunity.
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An inhibitor of Bcl-2 family proteins induces regression of solid tumours
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