Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-kappaB

Nat Cell Biol. 2001 Apr;3(4):409-16. doi: 10.1038/35070096.

Abstract

TRAIL (tumour-necrosis factor-related apoptosis ligand or Apo2L) triggers apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription factor NF-kappaB induces expression of TRAIL-R1 and TRAIL-R2; conversely, a transdominant mutant of the inhibitory protein IkappaBalpha or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-kappaB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-kappaB also increases expression of the apoptosis inhibitor, Bcl-xL, and protects cells from TRAIL. Inhibition of NF-kappaB by blocking activation of the IkappaB kinase complex reduces Bcl-x L expression and sensitizes tumour cells to TRAIL-induced apoptosis. The ability to induce death receptors or Bcl-xL may explain the dual roles of NF-kappaB as a mediator or inhibitor of cell death during immune and stress responses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation*
  • HeLa Cells
  • Humans
  • I-kappa B Proteins*
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / pharmacology
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-rel / genetics
  • Proto-Oncogene Proteins c-rel / metabolism*
  • Radiation Tolerance
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / genetics*
  • TNF-Related Apoptosis-Inducing Ligand
  • Transcription Factor RelA
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-X Protein

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-rel
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tnfrsf10b protein, mouse
  • Tnfsf10 protein, mouse
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • NF-KappaB Inhibitor alpha