Abstract
The proapoptotic mammalian protein Bax associates with mitochondrial membranes and confers a lethal phenotype when expressed in yeast. By generating Bax-resistant mutant yeast and using classical complementation cloning methods, subunits of the mitochondrial F0F1-ATPase proton pump were determined to be critical for Bax-mediated killing in S. cerevisiae. A pharmacological inhibitor of the proton pump, oligomycin, also partially abrogated the cytotoxic actions of Bax in yeast. In mammalian cells, oligomycin also inhibited Bax-induced apoptosis and activation of cell death proteases. The findings imply that an intact F0F1-ATPase in the inner membrane of mitochondria is necessary for optimal function of Bax in both yeast and mammalian cells.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Cell Respiration / drug effects
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Cell Respiration / physiology
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Cells, Cultured
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Cloning, Molecular
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Eukaryotic Cells / enzymology
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Genes, Fungal / physiology
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Genetic Complementation Test
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Kidney / cytology
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Mammals
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Mutation / physiology
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Oligomycins / pharmacology
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proton-Translocating ATPases / metabolism*
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Rats
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Saccharomyces cerevisiae / enzymology*
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Saccharomyces cerevisiae / genetics
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Tumor Suppressor Protein p53 / metabolism
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Uncoupling Agents / pharmacology
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bcl-2-Associated X Protein
Substances
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Bax protein, rat
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Oligomycins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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Uncoupling Agents
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bcl-2-Associated X Protein
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Proton-Translocating ATPases