Role of NF-kappaB in p53-mediated programmed cell death

Nature. 2000 Apr 20;404(6780):892-7. doi: 10.1038/35009130.


The tumour suppressor p53 inhibits cell growth through activation of cell-cycle arrest and apoptosis, and most cancers have either mutation within the p53 gene or defects in the ability to induce p53. Activation or re-introduction of p53 induces apoptosis in many tumour cells and may provide effective cancer therapy. One of the key proteins that modulates the apoptotic response is NF-kappaB, a transcription factor that can protect or contribute to apoptosis. Here we show that induction of p53 causes an activation of NF-kappaB that correlates with the ability of p53 to induce apoptosis. Inhibition or loss of NF-kappaB activity abrogated p53-induced apoptosis, indicating that NF-kappaB is essential in p53-mediated cell death. Activation of NF-kappaB by p53 was distinct from that mediated by tumour-necrosis factor-alpha and involved MEK1 and the activation of pp90rsk. Inhibition of MEK1 blocked activation of NF-kappaB by p53 and completely abrogated p53-induced cell death. We conclude that inhibition of NF-kappaB in tumours that retain wild-type p53 may diminish, rather than augment, a therapeutic response.

MeSH terms

  • Animals
  • Apoptosis*
  • Cloning, Molecular
  • DNA / metabolism
  • Humans
  • Mice
  • Mutation
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Protein Binding
  • Signal Transduction
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology*


  • NF-kappa B
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • DNA