Mitochondria Primed by Death Signals Determine Cellular Addiction to Antiapoptotic BCL-2 Family Members

Cancer Cell. 2006 May;9(5):351-65. doi: 10.1016/j.ccr.2006.03.027.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Bcl-2-Like Protein 11
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Enzyme Activators
  • Intracellular Membranes / metabolism
  • Leukemia / pathology
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism*
  • Mitochondrial Membranes / metabolism
  • Molecular Sequence Data
  • Nitrophenols
  • Peptide Fragments / chemistry
  • Piperazines
  • Protein Binding
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Signal Transduction*
  • Sulfonamides

Substances

  • ABT-737
  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Bax protein (53-86)
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Biphenyl Compounds
  • Enzyme Activators
  • Membrane Proteins
  • Nitrophenols
  • Peptide Fragments
  • Piperazines
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides