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Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor.

Nicolaides NC, Charmandari E, Chrousos GP, Kino T - BMC Endocr Disord (2014)

Bottom Line: The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action.The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor.Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens 11527, Greece. nnicolaides@bioacademy.gr.

ABSTRACT
Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor.

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CLOCK-mediated gene-specific regulation of glucocorticoid action in peripheral target tissues. Circulating cortisol concentrations in humans fluctuate diurnally, as indicated in the top panel. The expression of glucocorticoid-target genes is also expected to fluctuate depending on the changes of circulating cortisol concentrations. However, this diurnal fluctuation of gene expression is suppressed through acetylation of GR by locally expressed CLOCK/BMAL1 heterodimers, possibly functioning as a local counter-regulatory feedback loop to the circulating glucocorticoids. Thus, high levels of acetylated GR in the morning are associated with low target-tissue sensitivity to glucocorticoids and vice versa in the evening and early night. Modified from Reference [56].
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Figure 3: CLOCK-mediated gene-specific regulation of glucocorticoid action in peripheral target tissues. Circulating cortisol concentrations in humans fluctuate diurnally, as indicated in the top panel. The expression of glucocorticoid-target genes is also expected to fluctuate depending on the changes of circulating cortisol concentrations. However, this diurnal fluctuation of gene expression is suppressed through acetylation of GR by locally expressed CLOCK/BMAL1 heterodimers, possibly functioning as a local counter-regulatory feedback loop to the circulating glucocorticoids. Thus, high levels of acetylated GR in the morning are associated with low target-tissue sensitivity to glucocorticoids and vice versa in the evening and early night. Modified from Reference [56].

Mentions: We have recently demonstrated that CLOCK physically interacts with the LBD of the hGR and suppresses the hGR-induced transcriptional activity by acetylating multiple lysine residues (480, 492, 494, and 495) in the hinge region of the receptor. This post-translational modification attenuates the binding of hGR to GREs and its ability to influence glucocorticoid-responsive gene expression. Furthermore, the expression of glucocorticoid-responsive genes fluctuated in a circadian fashion, mirroring in reverse phase the Clock/Bmal1 expression [57]. These findings indicate that CLOCK/BMAL1 is a reverse-phase negative regulator of glucocorticoid action in target tissues, antagonizing the biologic actions of diurnally fluctuating circulating glucocorticoids and providing a local target tissue counter-regulatory feedback loop to the central clock influence on the HPA axis [57]. As a result, tissue sensitivity to glucocorticoids is decreased in the morning (when circulating cortisol concentrations are elevated) and increased in the evening and early night (when cortisol concentrations reach their nadir) (FigureĀ 3).


Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor.

Nicolaides NC, Charmandari E, Chrousos GP, Kino T - BMC Endocr Disord (2014)

CLOCK-mediated gene-specific regulation of glucocorticoid action in peripheral target tissues. Circulating cortisol concentrations in humans fluctuate diurnally, as indicated in the top panel. The expression of glucocorticoid-target genes is also expected to fluctuate depending on the changes of circulating cortisol concentrations. However, this diurnal fluctuation of gene expression is suppressed through acetylation of GR by locally expressed CLOCK/BMAL1 heterodimers, possibly functioning as a local counter-regulatory feedback loop to the circulating glucocorticoids. Thus, high levels of acetylated GR in the morning are associated with low target-tissue sensitivity to glucocorticoids and vice versa in the evening and early night. Modified from Reference [56].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4155765&req=5

Figure 3: CLOCK-mediated gene-specific regulation of glucocorticoid action in peripheral target tissues. Circulating cortisol concentrations in humans fluctuate diurnally, as indicated in the top panel. The expression of glucocorticoid-target genes is also expected to fluctuate depending on the changes of circulating cortisol concentrations. However, this diurnal fluctuation of gene expression is suppressed through acetylation of GR by locally expressed CLOCK/BMAL1 heterodimers, possibly functioning as a local counter-regulatory feedback loop to the circulating glucocorticoids. Thus, high levels of acetylated GR in the morning are associated with low target-tissue sensitivity to glucocorticoids and vice versa in the evening and early night. Modified from Reference [56].
Mentions: We have recently demonstrated that CLOCK physically interacts with the LBD of the hGR and suppresses the hGR-induced transcriptional activity by acetylating multiple lysine residues (480, 492, 494, and 495) in the hinge region of the receptor. This post-translational modification attenuates the binding of hGR to GREs and its ability to influence glucocorticoid-responsive gene expression. Furthermore, the expression of glucocorticoid-responsive genes fluctuated in a circadian fashion, mirroring in reverse phase the Clock/Bmal1 expression [57]. These findings indicate that CLOCK/BMAL1 is a reverse-phase negative regulator of glucocorticoid action in target tissues, antagonizing the biologic actions of diurnally fluctuating circulating glucocorticoids and providing a local target tissue counter-regulatory feedback loop to the central clock influence on the HPA axis [57]. As a result, tissue sensitivity to glucocorticoids is decreased in the morning (when circulating cortisol concentrations are elevated) and increased in the evening and early night (when cortisol concentrations reach their nadir) (FigureĀ 3).

Bottom Line: The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action.The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor.Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens 11527, Greece. nnicolaides@bioacademy.gr.

ABSTRACT
Glucocorticoids are pleiotropic hormones, which are involved in almost every cellular, molecular and physiologic network of the organism, and regulate a broad spectrum of physiologic functions essential for life. The cellular response to glucocorticoids displays profound variability both in magnitude and in specificity of action. Tissue sensitivity to glucocorticoids differs among individuals, within tissues of the same individual and within the same cell. The actions of glucocorticoids are mediated by the glucocorticoid receptor, a ubiquitously expressed intracellular, ligand-dependent transcription factor. Multiple mechanisms, such as pre-receptor ligand metabolism, receptor isoform expression, and receptor-, tissue-, and cell type-specific factors, exist to generate diversity as well as specificity in the response to glucocorticoids. Alterations in the molecular mechanisms of glucocorticoid receptor action impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. This review summarizes the recent advances in our understanding of the molecular mechanisms determining tissue sensitivity to glucocorticoids with particular emphasis on novel mutations and new information on the circadian rhythm and ligand-induced repression of the glucocorticoid receptor.

Show MeSH
Related in: MedlinePlus