RelB/p50 dimers are differentially regulated by tumor necrosis factor-alpha and lymphotoxin-beta receptor activation: critical roles for p100

J Biol Chem. 2003 Jun 27;278(26):23278-84. doi: 10.1074/jbc.M300106200. Epub 2003 Apr 21.

Abstract

Tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin-beta receptor (LTbetaR) signaling both play important roles in inflammatory and immune responses through activation of NF-kappaB. Using various deficient mouse embryonic fibroblast cells, we have compared the signaling pathways leading to NF-kappaB induction in response to TNF-alpha and LTbetaR activation. We demonstrate that LTbetaR ligation induces not only RelA/p50 dimers but also RelB/p50 dimers, whereas TNF-alpha induces only RelA/p50 dimers. LTbetaR-induced binding of RelB/p50 requires processing of p100 that is mediated by IKKalpha but is independent of IKKbeta, NEMO/IKKgamma, and RelA. Moreover, we show that RelB, p50, and p100 can associate in the same complex and that TNF-alpha but not LTbeta signaling increases the association of p100 with RelB/p50 dimers in the nucleus, leading to the specific inhibition of RelB DNA binding. These results suggest that the alternative NF-kappaB pathway based on p100 processing may account not only for the activation of RelB/p52 dimers but also for that of RelB/p50 dimers and that p100 regulates the binding activity of RelB/p50 dimers via at least two distinct mechanisms depending on the signaling pathway involved.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • DNA / metabolism
  • Dimerization
  • Endonucleases
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • I-kappa B Kinase
  • I-kappa B Proteins / metabolism
  • Lymphotoxin beta Receptor
  • Mice
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / physiology
  • Transcription Factor RelB
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • I-kappa B Proteins
  • Ltbr protein, mouse
  • Lymphotoxin beta Receptor
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Receptors, Tumor Necrosis Factor
  • Relb protein, mouse
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Transcription Factor RelB
  • DNA
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Endonucleases
  • Snd1 protein, mouse