p53 induces NF-kappaB activation by an IkappaB kinase-independent mechanism involving phosphorylation of p65 by ribosomal S6 kinase 1

J Biol Chem. 2004 Jun 18;279(25):26115-25. doi: 10.1074/jbc.M313509200. Epub 2004 Apr 8.

Abstract

Apoptosis induced by p53 has been proposed to involve activation of the transcription factor NF-kappaB. Here we describe the novel molecular mechanism through which p53 and DNA-damaging agents activate NF-kappaB. NF-kappaB induction by p53 does not occur through classical activation of the IkappaB kinases and degradation of IkappaBalpha. Rather, p53 expression stimulates the serine/threonine kinase ribosomal S6 kinase 1 (RSK1), which in turn phosphorylates the p65 subunit of NF-kappaB. The lower affinity of RSK1-phosphorylated p65 for its negative regulator, IkappaBalpha, decreases IkappaBalpha-mediated nuclear export of shuttling forms of NF-kappaB, thereby promoting the binding and action of NF-kappaB on cognate kappaB enhancers. These findings highlight a rather unusual pathway of NF-kappaB activation, which is utilized by the p53 tumor suppressor.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • DNA Damage
  • Enzyme Activation
  • Fibroblasts / metabolism
  • Gene Silencing
  • Genes, Reporter
  • Humans
  • I-kappa B Kinase
  • Mice
  • Models, Biological
  • Mutation
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Precipitin Tests
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Transcription Factor RelA
  • Transcription, Genetic
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • NF-kappa B
  • RNA, Small Interfering
  • Transcription Factor RelA
  • Tumor Suppressor Protein p53
  • Protein-Serine-Threonine Kinases
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse