Mechanisms of glucocorticoid signalling

Schoneveld, Onard J.L.M.; Gaemers, Ingrid C.; Lamers, Wouter H.

doi:10.1016/j.bbaexp.2004.09.004

Cited by 268 publications

(232 citation statements)

References 140 publications

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“…GC-dependent Transcription of the CALD1 Gene-GCs are reported to regulate the transcription of numerous GC-responsive genes, such as SGK1 (serum-and glucocorticoid-inducible kinase 1), IL-2R␣ (interleukin-2 receptor ␣), and proopiomelanocortin (10). However, few GC-responsive cytoskeletal genes are known.…”

Section: Discussionmentioning

confidence: 99%

“…Glucocorticoid receptor (GR) is critical for transduction of the GC signal (10,11) and is mainly located in the cytosol when not bound by ligands. Upon ligand binding, GR translocates into the nucleus, binds to the cognate DNA element (GC response element, GRE) within the promoter regions of target genes, and then activates or represses their transcription (10). Despite the many reports on the biological effects of GCs, their effect on cell motility has been little studied.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Animals (3-4 per time point) were sacrificed over a period of 72 hr for the single dose groups (0.25, 0.5, 0.75, 1, 2, 4, 5, 5. 5,6,7,8,12,18,24,30,36, 48 and 72 hr) and over a period of 120 hr (0. 25, 1, 3, 5, 6, 7, 8, 12, 18, 24, 24.25, 25, 27, 29, 30, 31, 32, 36, 42, 54, 72, 96 and 120 hr) for the dual dose group.…”

Section: Methodsmentioning

confidence: 99%

“…After dissociation from its plasma protein carrier, CS enter the cell by passive diffusion (6,7) and associate with heat-shock protein bound cytosolic GR, causing its dissociation from the heat-shock protein complex. Subsequently, the drug-receptor complex becomes activated, hyperphosphorylated and undergoes conformational changes (1,8). This activated drug-receptor complex translocates into the nucleus and binds to glucocorticoid response elements (GRE), specific DNA control regions (located at the 5′ site) of the target gene, resulting in increased or decreased transcription of various mRNAs.…”

Section: Introductionmentioning

confidence: 99%

Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling

Hazra

DuBois

Almon

et al. 2007

J Pharmacokinet Pharmacodyn

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A retrospective analysis was performed to modify our fourth-generation pharmacodynamic model for glucocorticoid receptor (GR) dynamics with incorporation of more physiological features. This modified model was developed by integrating previously reported free cytosolic GR and GR mRNA data following single (10, 50 mg/kg) and dual (50 mg/kg at 0 and 24 hr) intravenous doses of methylprednisolone (MPL) in adrenalectomized (ADX) male Wistar rats with several in vitro studies describing real-time kinetics of the transfer of rat steroid-receptor complex from the cell cytosol to the nucleus. Additionally, free hepatic cytosolic GR and its mRNA data from a chronic infusion dosing study of MPL (0.1 and 0.3 mg/kg/hr) in male ADX Wistar rats were used to verify the predictability of the model. Incorporation of information regarding in vitro receptor kinetics allowed us to describe the receptor-mediated pharmacogenomic effects of MPL for a larger variety of genes in rat liver from microarray studies. These included early responsive gene like CCAAT/ enhancer binding protein-β (CEBP-β), a transcription factor, as well as the later responsive gene for tyrosine aminotransferase (TAT), a classical biomarker of glucocorticoid (GC) genomic effects. This more mechanistic model of GR dynamics can be applied to characterize profiles for a greater number of genes in liver.

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“…The receptor conformation returns from a labile open structure into a stable compact DNA-binding state that can exist independently of chaperone complexes (Pratt & Toft 1997). Subsequently, the receptor is translocated into the nucleus, where it will homodimerise and bind as a homodimer to the specific DNA motifs (GREs) which in turn will activate transcription of the downstream genes (Schoneveld et al 2004). …”

Section: Ligand-binding Region and Heat Shock Proteins (Hsps)mentioning

confidence: 99%

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

Stolte¹,

Kemenade²,

Savelkoul³

et al. 2006

Journal of Endocrinology

148

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Glucocorticoids (GCs) are commonly used to treat a variety of immune diseases. However, the efficacy of treatment is greatly influenced by an individual variation in sensitivity to GCs, which is caused by differences in the glucocorticoid receptor (GR). The variable receptor profile results from variations in the GR gene, or alternative splicing of the gene coded. We investigated the evolution of the GR gene by comparing genomic GR sequences of vertebrates. Exon length and amino acid sequence are conserved among all classes of vertebrates studied, which indicates strong evolutionary pressure on conservation of this gene. Interestingly, teleostean fishes have two different GR proteins. One of the duplicate fish GR genes has a nine-amino-acid insert in the DNA binding region that results from alternative splicing. The duplicate GR genes and products of alternative splicing in teleostean fishes are differentially expressed in vivo and show different transactivation capacity in vitro. The presence of two GR genes appears to be a result of divergence of receptors rather than of ligands. Teleostean fishes express different, evolutionarily related, functional GR proteins within a single organism. Hereby, teleostean fishes present a model that facilitates investigation of the molecular basis of cortisol resistance and different regulatory functions of cortisol.

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Mechanisms of glucocorticoid signalling

Cited by 268 publications

References 140 publications

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

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

Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

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