NF-kappa B2 p100 is a pro-apoptotic protein with anti-oncogenic function

Nat Cell Biol. 2002 Nov;4(11):888-93. doi: 10.1038/ncb872.


Nuclear factor-kappa B (NF-kappa B) promotes cell survival by upregulating expression of anti-apoptotic genes, a process that is antagonized by inhibitors of kappa B (I kappa B) factors. The only NF-kappa B family member known to be mutated in human cancer is NF-kappa B2 p100 (ref. 2), a factor with I kappa B activity. Here, we report the isolation from irradiated mouse tumour cells of a complex that induces caspase-8 activity in cell-free assays and identify p100 as an essential component of this complex. Expression of p100 profoundly sensitizes cells to death-receptor-mediated apoptosis through a pathway that is independent of I kappa B-like activity. The carboxyl terminus of p100 contains a death domain that is absent from all known tumour-derived mutants. This death domain mediates recruitment of p100 into death machinery complexes after ligand stimulation and is essential for p100's pro-apoptotic activity. p100 also sensitizes NIH3T3 cells to apoptosis triggered by oncogenic Ras, resulting in a marked inhibition of transformation that is rescued by suppression of endogenous caspase-8. These observations thus identify an I kappa B-independent apoptotic activity of NF-kappa B2 p100 and help explain its unique tumour suppressor role.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 8
  • Caspases / metabolism
  • Cell Death
  • Cell Line, Tumor
  • Cell Survival
  • Cell-Free System
  • Colorimetry
  • Cycloheximide / pharmacology
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • Gene Transfer Techniques
  • Genes, Tumor Suppressor
  • Humans
  • Immunoblotting
  • Mass Spectrometry
  • Mice
  • Mutation
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • NF-kappa B p52 Subunit
  • NIH 3T3 Cells
  • Plasmids / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Retroviridae / genetics
  • Time Factors
  • Transfection
  • Up-Regulation


  • NF-kappa B
  • NF-kappa B p52 Subunit
  • Cycloheximide
  • CASP8 protein, human
  • Casp8 protein, mouse
  • Caspase 8
  • Caspases