A nuclear isoform of the focal adhesion LIM-domain protein Trip6 integrates activating and repressing signals at AP-1- and NF-kappaB-regulated promoters

Genes Dev. 2004 Oct 15;18(20):2518-28. doi: 10.1101/gad.322404.

Abstract

Glucocorticoid receptor (GR)-mediated transrepression of the transcription factors AP-1 and NF-kappaB, responsible for most of the anti-inflammatory effects of glucocorticoids, is initiated by the tethering of GR to the promoters of target genes. We report that this tethering is mediated by a nuclear isoform of the focal adhesion LIM domain protein Trip6. Trip6 functions as a coactivator for both AP-1 and NF-kappaB. As shown by chromatin immunoprecipitation, Trip6 is recruited to the promoters of target genes together with AP-1 or NF-kappaB. In the presence of glucocorticoids, GR joins the Trip6 complex. Reducing the level of Trip6 by RNA interference or abolishing its interaction with GR by dominant-negative mutation eliminates transrepression. We propose that GR tethering to the target promoter through Trip6 forms the basis of transrepression, and that Trip6 exerts its nuclear functions by acting as a molecular platform, enabling target promoters to integrate activating or repressing signals.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Cell Fractionation
  • Cells, Cultured
  • Chromatin / chemistry
  • DNA Primers
  • Gene Expression Regulation*
  • Glutathione Transferase
  • Humans
  • Immunoprecipitation
  • Luciferases
  • NF-kappa B / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Plasmids / genetics
  • Promoter Regions, Genetic / genetics*
  • Protein Isoforms / metabolism
  • RNA Interference
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Transcription Factor AP-1 / metabolism*
  • Two-Hybrid System Techniques

Substances

  • Chromatin
  • DNA Primers
  • NF-kappa B
  • Nuclear Proteins
  • Protein Isoforms
  • Receptors, Glucocorticoid
  • Transcription Factor AP-1
  • Luciferases
  • Glutathione Transferase