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Restriction to Fos Family Members of Trip6-Dependent Coactivation and Glucocorticoid Receptor-Dependent Trans-Repression of Activator Protein-1

Forschungszentrum Karlsruhe (M.D., S.S., C.H., J.V.M., M.L., P.H., O.K.), Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany; Department of Molecular Cell Biology (H.v.D.), Leiden University Medical Center, 2333AL Leiden, The Netherlands; Université de Lyon (M.C.), Institut National de la Santé et de la Recherche Médicale, Unité 758, Institut Fédératif de Recherche 128, Lyon-Gerland, France; and Leibniz Institute of Age Research-Fritz-Lipmann-Institute (P.H.), D-07745 Jena, Germany

Address all correspondence and requests for reprints to: Olivier Kassel, Institut für Toxikologie und Genetik, Forschungszentrum Karlsruhe, Hermann-von-Helmholtz Platz 1, D- 76344 Eggenstein-Leopoldshafen, Germany. E-mail: Olivier.Kassel{at}itg.fzk.de.

The term activator protein (AP)-1 describes homodimeric and heterodimeric transcription factors composed of members of the Jun, Fos, and cAMP response element-binding protein (CREB)/activating transcription factor (ATF) families of proteins. Distinct AP-1 dimers, for instance the prototypical c-Jun:c-Fos and c-Jun:ATF2 dimers, are differentially regulated by signaling pathways and bind related yet distinct response elements in the regulatory regions of AP-1 target genes. Little is known about the dimer-specific regulation of AP-1 activity at the promoter of its target genes. We have previously shown that nTrip6, the nuclear isoform of the LIM domain protein Trip6, acts as an AP-1 coactivator. Moreover, nTrip6 is an essential component of glucocorticoid receptor (GR)-mediated trans-repression of AP-1, in that it mediates the tethering of GR to the promoter-bound AP-1. We have now discovered a striking specificity of nTrip6 actions determined by the binding preference of its LIM domains. We show that nTrip6 interacts only with Fos family members. Consequently, nTrip6 is a selective coactivator for AP-1 dimers containing Fos. nTrip6 also assembles activated GR to c-Jun:c-Fos-driven promoters. Neither nTrip6 nor GR are recruited to a promoter occupied by c-Jun:ATF2. Thus, only Fos-containing dimers are trans-repressed by GR. Thus, the dimer composition of AP-1 determines the mechanism of both the positive and negative regulation of AP-1 transcriptional activity. Interestingly, on a second level of action, GR represses the increase in transcriptional activity of c-Jun:ATF2 induced by c-Jun N-terminal kinase (JNK)-dependent phosphorylation. This repression depends on GR-mediated induction of MAPK phosphatase 1 (MKP-1) expression, which results in c-Jun N-terminal kinase inactivation.

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Nuclear Receptors:   GR

Ligands:   Dexamethasone

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