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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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Μolecular mechanisms through which the natural mutant receptor hGRαV423A causes Chrousos syndrome. Both the wild-type hGRα and the mutant hGRαV423A reside in the cytoplasm in the absence of ligand by forming a heterocomplex with heat shock proteins (HSP) and FKBP51 (FKBP). Upon binding to ligand, the wild-type hGRα dissociates from the heterocomplex partners and translocates into the nucleus, while this process of the mutant hGRαV423A is significantly delayed. The wild-type hGRα stimulates or represses the transcriptional activity of glucocorticoid-responsive genes by attracting to GRE DNA several coactivators including the glucocorticoid receptor-interacting protein 1 (GRIP-1), or by interacting with other transcription factors, such as NF-κB and activator protein-1 (AP-1). The hGRαV423A demonstrates reduced transactivation activity due to decreased ability to interact with GREs, while its activity to repress the transcriptional activity of other transcription factors is preserved. The hGRαV423A does not exert a dominant negative effect upon the wild type-induced transactivation of glucocorticoid-responsive genes. WT: wild-type human glucocorticoid receptor; V423A: human glucocorticoid receptor V423A; HSP: heat shock proteins; FKBP: immunophilins; GRIP-1: glucocorticoid receptor-interacting protein 1; p65: transcription factor p65; p50: transcription factor p50.
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Figure 2: Μolecular mechanisms through which the natural mutant receptor hGRαV423A causes Chrousos syndrome. Both the wild-type hGRα and the mutant hGRαV423A reside in the cytoplasm in the absence of ligand by forming a heterocomplex with heat shock proteins (HSP) and FKBP51 (FKBP). Upon binding to ligand, the wild-type hGRα dissociates from the heterocomplex partners and translocates into the nucleus, while this process of the mutant hGRαV423A is significantly delayed. The wild-type hGRα stimulates or represses the transcriptional activity of glucocorticoid-responsive genes by attracting to GRE DNA several coactivators including the glucocorticoid receptor-interacting protein 1 (GRIP-1), or by interacting with other transcription factors, such as NF-κB and activator protein-1 (AP-1). The hGRαV423A demonstrates reduced transactivation activity due to decreased ability to interact with GREs, while its activity to repress the transcriptional activity of other transcription factors is preserved. The hGRαV423A does not exert a dominant negative effect upon the wild type-induced transactivation of glucocorticoid-responsive genes. WT: wild-type human glucocorticoid receptor; V423A: human glucocorticoid receptor V423A; HSP: heat shock proteins; FKBP: immunophilins; GRIP-1: glucocorticoid receptor-interacting protein 1; p65: transcription factor p65; p50: transcription factor p50.

Mentions: We have recently described a new case of Chrousos syndrome caused by a novel, heterozygous, point mutation (V423A) in the DBD of the hGRα, and investigated the molecular mechanisms through which the hGRαV423A affects glucocorticoid signal transduction. Compared with the wild-type receptor, the mutant receptor hGRαV423A demonstrated a significant reduction (72%) in its ability to transactivate glucocorticoid-responsive genes, impaired ability to bind to GREs and a marked delay (2.6-fold) in the time required to translocate into the nucleus. However, the hGRαV423A did not exert a dominant negative effect upon the wild-type hGRα, had a similar affinity for the ligand, and displayed a normal interaction with the glucocorticoid receptor-interacting protein-1 (GRIP1) coactivator (Figure 2) [47].


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)

Μolecular mechanisms through which the natural mutant receptor hGRαV423A causes Chrousos syndrome. Both the wild-type hGRα and the mutant hGRαV423A reside in the cytoplasm in the absence of ligand by forming a heterocomplex with heat shock proteins (HSP) and FKBP51 (FKBP). Upon binding to ligand, the wild-type hGRα dissociates from the heterocomplex partners and translocates into the nucleus, while this process of the mutant hGRαV423A is significantly delayed. The wild-type hGRα stimulates or represses the transcriptional activity of glucocorticoid-responsive genes by attracting to GRE DNA several coactivators including the glucocorticoid receptor-interacting protein 1 (GRIP-1), or by interacting with other transcription factors, such as NF-κB and activator protein-1 (AP-1). The hGRαV423A demonstrates reduced transactivation activity due to decreased ability to interact with GREs, while its activity to repress the transcriptional activity of other transcription factors is preserved. The hGRαV423A does not exert a dominant negative effect upon the wild type-induced transactivation of glucocorticoid-responsive genes. WT: wild-type human glucocorticoid receptor; V423A: human glucocorticoid receptor V423A; HSP: heat shock proteins; FKBP: immunophilins; GRIP-1: glucocorticoid receptor-interacting protein 1; p65: transcription factor p65; p50: transcription factor p50.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Μolecular mechanisms through which the natural mutant receptor hGRαV423A causes Chrousos syndrome. Both the wild-type hGRα and the mutant hGRαV423A reside in the cytoplasm in the absence of ligand by forming a heterocomplex with heat shock proteins (HSP) and FKBP51 (FKBP). Upon binding to ligand, the wild-type hGRα dissociates from the heterocomplex partners and translocates into the nucleus, while this process of the mutant hGRαV423A is significantly delayed. The wild-type hGRα stimulates or represses the transcriptional activity of glucocorticoid-responsive genes by attracting to GRE DNA several coactivators including the glucocorticoid receptor-interacting protein 1 (GRIP-1), or by interacting with other transcription factors, such as NF-κB and activator protein-1 (AP-1). The hGRαV423A demonstrates reduced transactivation activity due to decreased ability to interact with GREs, while its activity to repress the transcriptional activity of other transcription factors is preserved. The hGRαV423A does not exert a dominant negative effect upon the wild type-induced transactivation of glucocorticoid-responsive genes. WT: wild-type human glucocorticoid receptor; V423A: human glucocorticoid receptor V423A; HSP: heat shock proteins; FKBP: immunophilins; GRIP-1: glucocorticoid receptor-interacting protein 1; p65: transcription factor p65; p50: transcription factor p50.
Mentions: We have recently described a new case of Chrousos syndrome caused by a novel, heterozygous, point mutation (V423A) in the DBD of the hGRα, and investigated the molecular mechanisms through which the hGRαV423A affects glucocorticoid signal transduction. Compared with the wild-type receptor, the mutant receptor hGRαV423A demonstrated a significant reduction (72%) in its ability to transactivate glucocorticoid-responsive genes, impaired ability to bind to GREs and a marked delay (2.6-fold) in the time required to translocate into the nucleus. However, the hGRαV423A did not exert a dominant negative effect upon the wild-type hGRα, had a similar affinity for the ligand, and displayed a normal interaction with the glucocorticoid receptor-interacting protein-1 (GRIP1) coactivator (Figure 2) [47].

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