Document Detail


Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins.
MedLine Citation:
PMID:  19074266     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Normal cellular lifespan is contingent upon preserving outer mitochondrial membrane (OMM) integrity, as permeabilization promotes apoptosis. BCL-2 family proteins control mitochondrial outer membrane permeabilization (MOMP) by regulating the activation of the pro-apoptotic BCL-2 effector molecules, BAX and BAK. Sustainable cellular stress induces proteins (e.g., BID, BIM, and cytosolic p53) capable of directly activating BAX and/or BAK, but these direct activators are sequestered by the anti-apoptotic BCL-2 proteins (e.g., BCL-2, BCL-xL, and MCL-1). In the event of accumulated or marked cellular stress, a coordinated effort between previously sequestered and nascent BH3-only proteins inhibits the anti-apoptotic BCL-2 repertoire to promote direct activator protein-mediated MOMP. We examined the effect of ABT-737, a BCL-2 antagonist, and PUMA, a BH3-only protein that inhibits the entire anti-apoptotic BCL-2 repertoire, with cells and mitochondria that sequestered direct activator proteins. ABT-737 and PUMA cooperated with sequestered direct activator proteins to promote MOMP and apoptosis, which in the absence of ABT-737 or PUMA did not influence OMM integrity or cellular survival. Our data show that the induction of apoptosis by inhibition of the anti-apoptotic BCL-2 repertoire requires "covert" levels of direct activators of BAX and BAK at the OMM.
Authors:
Jerry E Chipuk; John C Fisher; Christopher P Dillon; Richard W Kriwacki; Tomomi Kuwana; Douglas R Green
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-12-12
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  105     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-24     Completed Date:  2009-01-27     Revised Date:  2012-11-16    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20327-32     Citation Subset:  IM    
Affiliation:
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis*
Apoptosis Regulatory Proteins / antagonists & inhibitors*
Cells, Cultured
Mice
Mitochondrial Membranes
Permeability
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
bcl-2 Homologous Antagonist-Killer Protein / metabolism*
bcl-2-Associated X Protein / metabolism*
Grant Support
ID/Acronym/Agency:
AI52735/AI/NIAID NIH HHS; CA69381/CA/NCI NIH HHS; F32 CA101444/CA/NCI NIH HHS; P30CA21765/CA/NCI NIH HHS; R01CA082491/CA/NCI NIH HHS; R01CA092035/CA/NCI NIH HHS; R21AG024478/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-2-Associated X Protein
Comments/Corrections

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