A nuclear isoform of the focal adhesion LIM-domain protein Trip6 integrates activating and repressing signals at AP-1- and NF-kappaB-regulated promoters.
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.
Kassel
Olivier
O
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany. Olivier.Kassel@itg.fzk.de
Schneider
Sandra
S
Heilbock
Christine
C
Litfin
Margarethe
M
Göttlicher
Martin
M
Herrlich
Peter
P
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002458:Cell Fractionation; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry; D017931:DNA Primers; D005786:Gene Expression Regulation; D005982:Glutathione Transferase; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D002843:Chromatin; D017931:DNA Primers; D016328:NF-kappa B; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D008156:Luciferases; D005982:Glutathione Transferase