BH3-only proteins in apoptosis and beyond: an overview

Oncogene. 2008 Dec;27 Suppl 1(Suppl 1):S2-19. doi: 10.1038/onc.2009.39.


BH3-only BCL-2 family proteins are effectors of canonical mitochondrial apoptosis. They discharge their pro-apoptotic functions through BH1-3 pro-apoptotic proteins such as BAX and BAK, while their activity is suppressed by BH1-4 anti-apoptotic BCL-2 family members. The precise mechanism by which BH3-only proteins mediate apoptosis remains unresolved. The existing data are consistent with three mutually non-exclusive models (1) displacement of BH1-3 proteins from complexes with BH1-4 proteins; (2) direct interaction with and conformational activation of BH1-3 proteins; and (3) membrane insertion and membrane remodeling. The BH3-only proteins appear to play critical roles in restraining cancer and inflammatory diseases such as rheumatoid arthritis. Molecules that mimic the effect of BH3-only proteins are being used in treatments against these diseases. The cell death activity of a subclass of BH3-only members (BNIP3 and BNIP3L) is linked to cardiomyocyte loss during heart failure. In addition to their established role in apoptosis, several BH3-only members also regulate diverse cellular functions in cell-cycle regulation, DNA repair and metabolism. Several members are implicated in the induction of autophagy and autophagic cell death, possibly through unleashing of the BH3-only autophagic effector Beclin 1 from complexes with BCL-2/BCL-xL. The Chapters included in the current Oncogene Review issues provide in-depth discussions on various aspects of major BH3-only proteins.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • Arthritis, Rheumatoid / metabolism
  • Autophagy / physiology
  • Caenorhabditis elegans Proteins / physiology
  • Cell Cycle / physiology
  • Cell Transformation, Neoplastic
  • Consensus Sequence / physiology*
  • Gene Expression Regulation
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Humans
  • Mammals / metabolism
  • Mice
  • Mitochondrial Membranes / metabolism
  • Molecular Sequence Data
  • Multigene Family
  • Peptide Fragments / chemistry
  • Peptide Fragments / physiology*
  • Protein Conformation
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / physiology*


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Bax protein (53-86)
  • Caenorhabditis elegans Proteins
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2