BH3-only protein Bmf mediates apoptosis upon inhibition of CAP-dependent protein synthesis

Cell Death Differ. 2010 Nov;17(11):1672-83. doi: 10.1038/cdd.2010.97. Epub 2010 Aug 13.


Tight transcriptional regulation, alternative splicing and/or post-translational modifications of BH3-only proteins fine-tune their proapoptotic function. In this study, we characterize the gene locus of the BH3-only protein Bmf (Bcl-2-modifying factor) and describe the generation of two major isoforms from a common transcript in which initiation of protein synthesis involves leucine-coding CUG. Bmf(CUG) and the originally described isoform, Bmf-short, display comparable binding affinities to prosurvival Bcl-2 family members, localize preferentially to the outer mitochondrial membrane and induce rapid Bcl-2-blockable apoptosis. Notably, endogenous Bmf expression is induced on forms of cell stress known to cause repression of the CAP-dependent translation machinery such as serum deprivation, hypoxia, inhibition of the PI3K/AKT pathway or mTOR, as well as direct pharmacological inhibition of the eukaryotic translation initiation factor eIF-4E. Knock down or deletion of Bmf reduces apoptosis under some of these conditions, demonstrating that Bmf can act as a sentinel for stress-impaired CAP-dependent protein translation machinery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alternative Splicing
  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis* / genetics
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Base Sequence
  • Bcl-2-Like Protein 11
  • Cell Line
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Genes, bcl-2
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondrial Membranes / metabolism
  • Protein Biosynthesis
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Cap-Binding Proteins / genetics
  • RNA Cap-Binding Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription, Genetic
  • bcl-Associated Death Protein / metabolism


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BMF protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Bmf protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Membrane Proteins
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA Cap-Binding Proteins
  • RNA, Messenger
  • bcl-Associated Death Protein
  • MTOR protein, human
  • TOR Serine-Threonine Kinases