Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members.
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.
Certo
Michael
M
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Del Gaizo Moore
Victoria
V
Nishino
Mari
M
Wei
Guo
G
Korsmeyer
Stanley
S
Armstrong
Scott A
SA
Letai
Anthony
A
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D020536:Enzyme Activators; D007425:Intracellular Membranes / Q000378:metabolism; D007938:Leukemia / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D009596:Nitrophenols; D010446:Peptide Fragments / Q000737:chemistry; D010879:Piperazines; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides
C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C474007:Bax protein (53-86); D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001713:Biphenyl Compounds; D020536:Enzyme Activators; D008565:Membrane Proteins; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides