Abstract
We show that the antiapoptotic proteins BCL-2, BCL-XL, MCL-1, BFL-1, and BCL-w each bear a unique pattern of interaction with a panel of peptides derived from BH3 domains of BH3-only proteins. Cellular dependence on an antiapoptotic protein for survival can be decoded based on the pattern of mitochondrial sensitivity to this peptide panel, a strategy that we call BH3 profiling. Dependence on antiapoptotic proteins correlates with sequestration of activator BH3-only proteins like BID or BIM by antiapoptotic proteins. Sensitivity to the cell-permeable BCL-2 antagonist ABT-737 is also related to priming of BCL-2 by activator BH3-only molecules. Our data allow us to distinguish a cellular state we call "primed for death," which can be determined by BH3 profiling and which correlates with dependence on antiapoptotic family members for survival.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis*
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BH3 Interacting Domain Death Agonist Protein / metabolism
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Bcl-2-Like Protein 11
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Biphenyl Compounds / pharmacology
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Cell Line, Tumor
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Enzyme Activators
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Intracellular Membranes / metabolism
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Leukemia / pathology
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Membrane Proteins / metabolism
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Mice
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Mitochondria, Liver / drug effects
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Mitochondria, Liver / metabolism*
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Mitochondrial Membranes / metabolism
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Molecular Sequence Data
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Nitrophenols
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Peptide Fragments / chemistry
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Piperazines
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Protein Binding
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Signal Transduction*
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Sulfonamides
Substances
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ABT-737
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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Bax protein (53-86)
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Biphenyl Compounds
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Enzyme Activators
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Membrane Proteins
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Nitrophenols
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Peptide Fragments
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides