Kinetics of glucocorticoid-receptor complexes in rat thymus cells

Munck, Allan; Foley, Rosemary

doi:10.1016/0022-4731(76)90042-x

Cited by 65 publications

(28 citation statements)

References 12 publications

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“…This model is in line with recent results on GR and multiple KLFs (Chen et al 2013;Sasse et al 2013;Chinenov et al 2014) and has been proposed as a more general property of transcriptional regulation by nuclear receptors (Sasse and Gerber 2015). FFL architectures that require both GR and a downstream TF to be present for transcriptional regulation would reserve overarching regulatory control for GR, which is well attuned to ligand availability (Munck and Foley 1976). In this manner, transcriptional regulation by collaborative interactions with GR could be rapidly throttled as GC levels attenuate.…”

Section: Discussionsupporting

confidence: 84%

Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

et al. 2018

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Glucocorticoids are potent steroid hormones that regulate immunity and metabolism by activating the transcription factor (TF) activity of glucocorticoid receptor (GR). Previous models have proposed that DNA binding motifs and sites of chromatin accessibility predetermine GR binding and activity. However, there are vast excesses of both features relative to the number of GR binding sites. Thus, these features alone are unlikely to account for the specificity of GR binding and activity. To identify genomic and epigenetic contributions to GR binding specificity and the downstream changes resultant from GR binding, we performed hundreds of genome-wide measurements of TF binding, epigenetic state, and gene expression across a 12-h time course of glucocorticoid exposure. We found that glucocorticoid treatment induces GR to bind to nearly all pre-established enhancers within minutes. However, GR binds to only a small fraction of the set of accessible sites that lack enhancer marks. Once GR is bound to enhancers, a combination of enhancer motif composition and interactions between enhancers then determines the strength and persistence of GR binding, which consequently correlates with dramatic shifts in enhancer activation. Over the course of several hours, highly coordinated changes in TF binding and histone modification occupancy occur specifically within enhancers, and these changes correlate with changes in the expression of nearby genes. Following GR binding, changes in the binding of other TFs precede changes in chromatin accessibility, suggesting that other TFs are also sensitive to genomic features beyond that of accessibility.

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Section: Discussionsupporting

confidence: 84%

Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

et al. 2018

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“…Similar to the interaction of GR with GREs, ligands interact dynamically with the glucocorticoid receptor in vivo; the synthetic glucocorticoid dexamethasone (Dex) dissociates with a half-time of ϳ10 min, whereas the natural hormone cortisol dissociates with half-time of a few minutes (21). In contrast, purified hormone-receptor complexes are stable, consistent with crystallographic studies showing that the ligand is buried within the hydrophobic core of the LBD (4,38).…”

mentioning

confidence: 63%

The Ligand Binding Domain Controls Glucocorticoid Receptor Dynamics Independent of Ligand Release

Meijsing

Elbi

Luecke

et al. 2007

Molecular and Cellular Biology

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Ligand binding to the glucocorticoid receptor (GR) results in receptor binding to glucocorticoid response elements (GREs) and the formation of transcriptional regulatory complexes. Equally important, these complexes are continuously disassembled, with active processes driving GR off GREs. We found that cochaperone p23-dependent disruption of GR-driven transcription depended on the ligand binding domain (LBD). Next, we examined the importance of the LBD and of ligand dissociation in GR-GRE dissociation in living cells. We showed in fluorescence recovery after photobleaching studies that dissociation of GR from GREs is faster in the absence of the LBD. Furthermore, GR interaction with a target promoter revealed ligand-specific exchange rates. However, using covalently binding ligands, we demonstrated that ligand dissociation is not required for receptor dissociation from GREs. Overall, these studies showed that activities impinging on the LBD regulate GR exchange with GREs but that the dissociation of GR from GREs is independent from ligand dissociation.

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“…2B). Because DEX has a higher affinity for GR than cortisol (43), DEX induced CaD expression more strongly.…”

Section: Glucocorticoids Suppress Cell Migration and Reorganize The Amentioning

confidence: 99%

Glucocorticoid Receptor-mediated Expression of Caldesmon Regulates Cell Migration via the Reorganization of the Actin Cytoskeleton

Mayanagi¹,

Morita

Hayashi

et al. 2008

Journal of Biological Chemistry

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Glucocorticoids (GCs) play important roles in numerous cellular processes, including growth, development, homeostasis, inhibition of inflammation, and immunosuppression. Here we found that GC-treated human lung carcinoma A549 cells exhibited the enhanced formation of the thick stress fibers and focal adhesions, resulting in suppression of cell migration. In a screen for GC-responsive genes encoding actin-interacting proteins, we identified caldesmon (CaD), which is specifically up-regulated in response to GCs. CaD is a regulatory protein involved in actomyosin-based contraction and the stability of actin filaments. We further demonstrated that the up-regulation of CaD expression was controlled by glucocorticoid receptor (GR). An activated form of GR directly bound to the two glucocorticoidresponse element-like sequences in the human CALD1 promoter and transactivated the CALD1 gene, thereby up-regulating the CaD protein. Forced expression of CaD, without GC treatment, also enhanced the formation of thick stress fibers and focal adhesions and suppressed cell migration. Conversely, depletion of CaD abrogated the GC-induced phenotypes. The results of this study suggest that the GR-dependent up-regulation of CaD plays a pivotal role in regulating cell migration via the reorganization of the actin cytoskeleton.

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Kinetics of glucocorticoid-receptor complexes in rat thymus cells

Cited by 65 publications

References 12 publications

Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

The Ligand Binding Domain Controls Glucocorticoid Receptor Dynamics Independent of Ligand Release

Glucocorticoid Receptor-mediated Expression of Caldesmon Regulates Cell Migration via the Reorganization of the Actin Cytoskeleton

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