Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis

J Cell Biol. 2007 Nov 19;179(4):701-15. doi: 10.1083/jcb.200703040.

Abstract

B cell lymphoma 2 (Bcl-2) homology domain 3 (BH3)-only proteins of the Bcl-2 family are important functional adaptors that link cell death signals to the activation of Bax and/or Bak. The BH3-only protein Nbk/Bik induces cell death via an entirely Bax-dependent/Bak-independent mechanism. In contrast, cell death induced by the short splice variant of Bcl-x depends on Bak but not Bax. This indicates that Bak is functional but fails to become activated by Nbk. Here, we show that binding of myeloid cell leukemia 1 (Mcl-1) to Bak persists after Nbk expression and inhibits Nbk-induced apoptosis in Bax-deficient cells. In contrast, the BH3-only protein Puma disrupts Mcl-1-Bak interaction and triggers cell death via both Bax and Bak. Targeted knockdown of Mcl-1 overcomes inhibition of Bak and allows for Bak activation by Nbk. Thus, Nbk is held in check by Mcl-1 that interferes with activation of Bak. The finding that different BH3-only proteins rely specifically on Bax, Bak, or both has important implications for the design of anticancer drugs targeting Bcl-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis* / genetics
  • Apoptosis* / physiology
  • Benzimidazoles
  • Carbocyanines
  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cytochromes c / metabolism
  • Fluorescent Dyes
  • HCT116 Cells
  • Humans
  • Kidney / cytology
  • Male
  • Membrane Proteins / metabolism*
  • Mitochondria / physiology
  • Mitochondrial Proteins
  • Models, Biological
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism*
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Transgenes
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism*
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • BIK protein, human
  • Benzimidazoles
  • Carbocyanines
  • Fluorescent Dyes
  • Membrane Proteins
  • Mitochondrial Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine
  • Cytochromes c