Restriction to Fos family members of Trip6-dependent coactivation and glucocorticoid receptor-dependent Trans-repression of activator protein-1

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Abstract

The term activator protein (AP)-1 describes ho-modimeric 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 co-activator. 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. Copyright © 2008 by The Endocrine Society.

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Diefenbacher, M., Sekula, S., Heilbock, C., Maier, J. V., Litfin, M., Van Dam, H., … Kassel, O. (2008). Restriction to Fos family members of Trip6-dependent coactivation and glucocorticoid receptor-dependent Trans-repression of activator protein-1. Molecular Endocrinology, 22(8), 1767–1780. https://doi.org/10.1210/me.2007-0574

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