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RESEARCH PAPER
B-regulated promoters
1 Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany; 2 Institut für Molekulare Biotechnologie, D-07745 Jena, Germany
Glucocorticoid receptor (GR)-mediated transrepression of the transcription factors AP-1 and NF-
B, 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-B. As shown by chromatin immunoprecipitation, Trip6 is recruited to the promoters of target genes together with AP-1 or NF-B. 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.
[Keywords: Glucocorticoids; LIM domains; transactivation; repression; chromatin immunoprecipitation]
Received March 19, 2004; revised version accepted August 24, 2004.
3 These authors contributed equally to this work.
6 Corresponding author. E-MAIL Olivier.Kassel{at}itg.fzk.de; FAX 49 7247 823354.
4 Present address: Ganymed Pharmaceuticals AG, Freiligratstr. 12, D-55131 Mainz, Germany
5 Present address: GSF—Institut für Toxikologie, Ingolstädter Landstraße 1 D-85764 Neuherberg, Germany
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