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PMID: 20404322 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Regulation of mitochondrial apoptotic events by p53-mediated disruption of complexes between antiapoptotic Bcl-2 members and Bim.

The Journal of biological chemistry ·Vol. 285 ·No. 29 ·2010-07-16 ·Pages 22473-83

Han J, Goldstein LA, Hou W, Gastman BR, Rabinowich H

Abstract

Multiple mechanisms have been proposed for the mitochondrial function of p53 that are either dependent on or independent of its transcriptional activity. However, none of these mechanisms involves Bim functioning downstream of p53 mitochondrial translocation. Utilizing a p53 nuclear localization signal mutant, whose nuclear import is completely abrogated, we demonstrate that its apoptotic activity at the outer mitochondrial membrane, which involves conformational changes in Bax and Bak, is mediated by Bim. We further demonstrate an inverse correlation between the binding levels of p53 and Bim to Mcl-1. Thus, enhanced binding of p53 to Mcl-1 involves the disruption of existing complexes between Mcl-1 and Bim. We propose that mitochondrial p53 functions as a Bim derepressor by releasing Bim from sequestrating complexes with Mcl-1, Bcl-2, and Bcl-XL, and allowing its engagement in Bak/Bax activation.

MeSH Terms
Apoptosis Apoptosis Regulatory Proteins/metabolism Bcl-2-Like Protein 11 Binding, Competitive Cell Line, Tumor Humans Immunoprecipitation Membrane Potential, Mitochondrial Membrane Proteins/metabolism Mitochondria/metabolism Models, Biological Mutation/genetics Myeloid Cell Leukemia Sequence 1 Protein Nuclear Localization Signals/metabolism Protein Binding Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-bcl-2/metabolism Stress, Physiological Subcellular Fractions/metabolism Tumor Suppressor Protein p53/metabolism bcl-X Protein/metabolism
Chemicals
Apoptosis Regulatory Proteins BBC3 protein, human BCL2L11 protein, human Bcl-2-Like Protein 11 Membrane Proteins Myeloid Cell Leukemia Sequence 1 Protein Nuclear Localization Signals PMAIP1 protein, human Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Tumor Suppressor Protein p53 bcl-X Protein
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Han Jie
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Goldstein Leslie A
Hou Wen
Gastman Brian R
Rabinowich Hannah
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M109.081042
Published
2010-07-16
Epub
2010-00-19
Pages
22473-83
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2903343
Subset
IM
Grants
NCI NIH HHS · R01 CA132796 · United States
NCI NIH HHS · R01 CA109285 · United States
NCI NIH HHS · T32 CA060397 · United States
NCI NIH HHS · R01 CA111786 · United States
NCI NIH HHS · R01 CA132796-05 · United States
External Links
PubMed source DOI: 10.1074/jbc.M109.081042 PMC Full Text View journal details
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