Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies

Nat Cell Biol. 2006 Dec;8(12):1348-58. doi: 10.1038/ncb1499. Epub 2006 Nov 19.

Abstract

Although the BCL-2 family constitutes a crucial checkpoint in apoptosis, the intricate interplay between these family members remains elusive. Here, we demonstrate that BIM and PUMA, similar to truncated BID (tBID), directly activate BAX-BAK to release cytochrome c. Conversely, anti-apoptotic BCL-2-BCL-X(L)-MCL-1 sequesters these 'activator' BH3-only molecules into stable complexes, thus preventing the activation of BAX-BAK. Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-X(L)-MCL-1. Anti-apoptotic BCL-2 members are differentially inactivated by the remaining 'inactivator' BH3-only molecules including BAD, NOXA, BMF, BIK/BLK and HRK/DP5. BAD displaces tBID, BIM or PUMA from BCL-2-BCL-X(L) to activate BAX-BAK, whereas NOXA specifically antagonizes MCL-1. Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK. Our data establish a hierarchical regulation of mitochondrion-dependent apoptosis by various BCL-2 subfamilies.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Bcl-2-Like Protein 11
  • Cytochromes c / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / metabolism*
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Tumor Suppressor Proteins / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Mcl1 protein, mouse
  • Membrane Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • PUMA protein, mouse
  • Pmaip1 protein, mouse
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Cytochromes c