title: The LIM domain protein nTRIP6 recruits the mediator complex to AP-1-regulated promoters.
abstract: Several LIM domain proteins regulate transcription. They are thought to act through their LIM protein-protein interaction domains as adaptors for the recruitment of transcriptional co-regulators. An intriguing example is nTRIP6, the nuclear isoform of the focal adhesion protein TRIP6. nTRIP6 interacts with AP-1 and enhances its transcriptional activity. nTRIP6 is also essential for the transrepression of AP-1 by the glucocorticoid receptor (GR), by mediating GR tethering to promoter-bound AP-1. Here we report on the molecular mechanism by which nTRIP6 exerts these effects. Both the LIM domains and the pre-LIM region of nTRIP6 are necessary for its co-activator function for AP-1. Discrete domains within the pre-LIM region mediate the dimerization of nTRIP6 at the promoter, which enables the recruitment of the Mediator complex subunits THRAP3 and Med1. This recruitment is blocked by GR, through a competition between GR and THRAP3 for the interaction with the LIM domains of nTRIP6. Thus, nTRIP6 both positively and negatively regulates transcription by orchestrating the recruitment of the Mediator complex to AP-1-regulated promoters.
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics, Karlsruhe, Germany.
authors.forename: Markus E
authors.initials: ME
authors.lastname: Diefenbacher
authors.affiliation: Leibniz Institute for Age Research (Fritz Lipmann Institute), Jena, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Reich
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics, Karlsruhe, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dahley
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics, Karlsruhe, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Kemler
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics, Karlsruhe, Germany.
authors.forename: Margarethe
authors.initials: M
authors.lastname: Litfin
authors.affiliation: Leibniz Institute for Age Research (Fritz Lipmann Institute), Jena, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Herrlich
authors.affiliation: Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics, Karlsruhe, Germany.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kassel
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins / Q000737:chemistry / Q000378:metabolism*; D056892:Mediator Complex / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D056892:Mediator Complex; C092282:PSMC5 protein, human; D011965:Receptors, Glucocorticoid; C475774:THRAP3 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities