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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2008-11-10
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pubmed:abstractText |
Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) is a member of the Bcl-2 homology domain 3-only subfamily of proapoptotic Bcl-2 proteins and is associated with cell death in the myocardium. In this study, we investigated the potential mechanism(s) by which Bnip3 activity is regulated. We found that Bnip3 forms a DTT-sensitive homodimer that increased after myocardial ischemia-reperfusion (I/R). The presence of the antioxidant N-acetylcysteine reduced I/R-induced homodimerization of Bnip3. Overexpression of Bnip3 in cells revealed that most of exogenous Bnip3 exists as a DTT-sensitive homodimer that correlated with increased cell death. In contrast, endogenous Bnip3 existed mainly as a monomer under normal conditions in the heart. Screening of the Bnip3 protein sequence revealed a single conserved cysteine residue at position 64. Mutation of this cysteine to alanine (Bnip3C64A) or deletion of the NH2-terminus (amino acids 1-64) resulted in reduced cell death activity of Bnip3. Moreover, mutation of a histidine residue in the COOH-terminal transmembrane domain to alanine (Bnip3H173A) almost completely inhibited the cell death activity of Bnip3. Bnip3C64A had a reduced ability to interact with Bnip3, whereas Bnip3H173A was completely unable to interact with Bnip3, suggesting that homodimerization is important for Bnip3 function. A consequence of I/R is the production of reactive oxygen species and oxidation of proteins, which promotes the formation of disulfide bonds between proteins. Thus, these experiments suggest that Bnip3 functions as a redox sensor where increased oxidative stress induces homodimerization and activation of Bnip3 via cooperation of the NH2-terminal cysteine residue and the COOH-terminal transmembrane domain.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-10381623,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-10625696,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-10891486,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-11550088,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-11916965,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-12169648,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-12226479,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-12234769,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-12574146,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-14532263,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-14734800,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-15004034,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-15242736,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-15299040,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-15592527,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-16337153,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-16645637,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-16943242,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-16987017,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-17311347,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-17412696,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-17447897,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-17600828,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-17638546,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-17909626,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-18059169,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-18096822,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-2744487,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-7914839,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-8635213,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-8636421,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-9299379,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-9396766,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-9501201,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18790835-9575197
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0363-6135
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
295
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
H2025-31
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pubmed:dateRevised |
2010-9-21
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pubmed:meshHeading |
pubmed-meshheading:18790835-Animals,
pubmed-meshheading:18790835-Apoptosis,
pubmed-meshheading:18790835-Cysteine,
pubmed-meshheading:18790835-Disease Models, Animal,
pubmed-meshheading:18790835-HeLa Cells,
pubmed-meshheading:18790835-Humans,
pubmed-meshheading:18790835-Male,
pubmed-meshheading:18790835-Membrane Proteins,
pubmed-meshheading:18790835-Mice,
pubmed-meshheading:18790835-Mitochondria, Heart,
pubmed-meshheading:18790835-Mutation,
pubmed-meshheading:18790835-Myocardial Reperfusion Injury,
pubmed-meshheading:18790835-Myocytes, Cardiac,
pubmed-meshheading:18790835-Oxidation-Reduction,
pubmed-meshheading:18790835-Oxidative Stress,
pubmed-meshheading:18790835-Perfusion,
pubmed-meshheading:18790835-Protein Multimerization,
pubmed-meshheading:18790835-Protein Structure, Tertiary,
pubmed-meshheading:18790835-Proto-Oncogene Proteins,
pubmed-meshheading:18790835-Rats,
pubmed-meshheading:18790835-Rats, Sprague-Dawley,
pubmed-meshheading:18790835-Reactive Oxygen Species,
pubmed-meshheading:18790835-Recombinant Fusion Proteins,
pubmed-meshheading:18790835-Transfection
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pubmed:year |
2008
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pubmed:articleTitle |
Bnip3 functions as a mitochondrial sensor of oxidative stress during myocardial ischemia and reperfusion.
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pubmed:affiliation |
BioScience Center, San Diego State University, 5500 Campanile Dr., San Diego, CA 92182-4650, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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