Cross-talk between glucocorticoid receptor and AP-1

Herrlich, Peter

doi:10.1038/sj.onc.1204388

Cited by 211 publications

(133 citation statements)

References 116 publications

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“…The third class consisted of repressive interactions between AP-1 factors and nuclear receptors (seven pairs). Consistent with this result, AP-1 factors and the nuclear receptors PR, GR, and ER have been shown to mutually inhibit each other's ability to activate transcription (86,87). Finally, the fourth class contained repressive interactions involving Myb (four pairs; Fig.…”

Section: Synergistic and Inhibitory Interactions Occur In Synthetic Esupporting

confidence: 63%

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Grossman

Zhang

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

161

142

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Enhancers regulate gene expression through the binding of sequence-specific transcription factors (TFs) to cognate motifs. Various features influence TF binding and enhancer function-including the chromatin state of the genomic locus, the affinities of the binding site, the activity of the bound TFs, and interactions among TFs. However, the precise nature and relative contributions of these features remain unclear. Here, we used massively parallel reporter assays (MPRAs) involving 32,115 natural and synthetic enhancers, together with high-throughput in vivo binding assays, to systematically dissect the contribution of each of these features to the binding and activity of genomic regulatory elements that contain motifs for PPARγ, a TF that serves as a key regulator of adipogenesis. We show that distinct sets of features govern PPARγ binding vs. enhancer activity. PPARγ binding is largely governed by the affinity of the specific motif site and higher-order features of the larger genomic locus, such as chromatin accessibility. In contrast, the enhancer activity of PPARγ binding sites depends on varying contributions from dozens of TFs in the immediate vicinity, including interactions between combinations of these TFs. Different pairs of motifs follow different interaction rules, including subadditive, additive, and superadditive interactions among specific classes of TFs, with both spatially constrained and flexible grammars. Our results provide a paradigm for the systematic characterization of the genomic features underlying regulatory elements, applicable to the design of synthetic regulatory elements or the interpretation of human genetic variation.gene regulation | transcription factor binding | systems biology

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Section: Synergistic and Inhibitory Interactions Occur In Synthetic Esupporting

confidence: 63%

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Grossman

Zhang

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

161

142

View full text Add to dashboard Cite

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“…As noted above, all of these mechanisms have been suggested, and some evidence has been found in support (49, 60 -62). Although it has been suggested that GR might repress NF-B-mediated transcription by up-regulation of a specific inhibitor, I B (63), this explanation is inconsistent with the observation that dimerization-defective GR mutants are capable of repression (43,62). Furthermore, the suggestion that GR might block AP-1 or NF-B binding to FIG.…”

Section: Glucocorticoid Receptor Ligand-binding Domain Is Required Focontrasting

confidence: 49%

“…their target genes has also been excluded (62,64). Although there are reports that GR and AP-1 might compete for the common co-activator CREB-binding protein or p300 (65,66), other studies have suggested that this is not the case (47,51).…”

Section: Glucocorticoid Receptor Ligand-binding Domain Is Required Fomentioning

confidence: 99%

Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-β Action

Wang

Gelehrter

2003

Journal of Biological Chemistry

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The transforming growth factor-␤ (TGF-␤) and glucocorticoid signaling pathways interact both positively and negatively in regulating a variety of physiological and pathologic processes. We previously reported that liganded glucocorticoid receptor (GR) repressed TGF-␤ induction of human plasminogen activator inhibitor-1 gene transcription by directly targeting the transcriptional activation function of Smad3. To identify the domain(s) in the glucocorticoid receptor involved in this repression, we have examined the ability of various GR truncation, deletion, and substitution mutants to repress TGF-␤ transactivation in Hep3B human hepatoma cells that lack functional endogenous GR. Partial deletions in the ligand-binding domain (LBD), including the 2 and c regions, greatly reduced or eliminated GR repression, whereas deletion of the N-terminal AF1 ( 1) domain and substitution mutations in the DNA-binding domain had little or no effect. Liganded androgen receptor repressed TGF-␤ transactivation, whereas mineralocorticoid receptor did not, and studies with rat GRmineralocorticoid receptor chimeras confirmed that the GR C-terminal domains were required for repression. RU486, a strong antagonist of transactivation by GR, partially reversed repression by wild type GR. Co-immunoprecipitation experiments in Hep3B cells indicated that physical interaction between GR and Smad3 is necessary but not sufficient for repression. Physical interaction required activation of Smad3 by TGF-␤ but not dexamethasone binding to GR. Glutathione S-transferase pull-down assays demonstrated that several regions of the LBD could mediate GR-Smad3 physical interaction. We conclude that the LBD of GR, but not the DNAbinding domain or the N-terminal activation domain, is required for GR-mediated transrepression of TGF-␤ transactivation.

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“…AP-1 represents a set of dimeric complexes composed of members of the Jun, Fos and ATF families, which assemble into homo-(Jun/Jun) or heterodimers (Jun/ Fos, Jun/Fra, Jun/ATF; van Dam and Castellazzi, 2001), and synergize or interfere with other transcription factors (Chinenov and Kerppola, 2001;Herrlich, 2001). AP-1 mediates gene expression in response to a variety of stimuli, including growth factors, cytokines, oncoproteins and chemical carcinogens (Angel et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing

et al. 2004

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Cross-talk between glucocorticoid receptor and AP-1

Cited by 211 publications

References 116 publications

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-β Action

Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing

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