Regulation of the human glucocorticoid receptor by long-term and chronic treatment with glucocorticoid

Silva, Corinne M.; Powell-Oliver, Frances E.; Jewell, Christine M.; Sar, Madhabanada; Allgood, Victoria E.; Cidlowski, John A.

doi:10.1016/0039-128x(94)90013-2

Cited by 118 publications

(81 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Table 2 Correlations between serum cortisol concentrations and cortisol receptor characteristics in patients with Cushing's syndrome (n = 13) and in control subjects (n = 14). (7,8). The possible mechanism of this receptor downregulation is poorly understood.…”

Section: European Journal Of Endocrinology (2000) 142mentioning

confidence: 99%

“…It is now well established that the ability of GCs to exert their biological effects requires the presence of a sufficient amount of intact receptor molecules (4,6). There is evidence that GRs undergo down-regulation after exposure to ligand in vitro, in animals and men (7,8). This receptor down-regulation is supposed to be an additional form of negative feedback regulation of GC action, apart from the regulation of GC serum levels by the HPA-axis (6).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Huizenga¹,

Herder²,

Koper³

et al. 2000

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: Glucocorticoids (GCs) serve a variety of important functions throughout the body. The synthesis and secretion of GCs are under the strict influence of the hypothalamo-pituitary-adrenal axis. The mechanisms of action of GCs are mediated by the intracellular glucocorticoid receptor (GR). Over the years, many studies have been performed concerning the regulation of GR expression by GC concentrations. Methods: In the present study, we determined the characteristics of the GR in peripheral mononuclear blood leukocytes (PBML) from thirteen patients with endogenous Cushing's syndrome and fifteen control subjects, using a whole cell dexamethasone binding assay. Furthermore, cortisol concentrations were determined in order to investigate a possible relationship between serum cortisol levels and receptor characteristics. Results: There were no differences in mean receptor number between patients and controls. On the other hand, a significantly lower ligand affinity was identified in cells from patients with Cushing's syndrome compared with controls. A complete normalisation of the ligand affinity was observed after treatment in the only patient tested in this respect, whereas the receptor number was not affected. In patients, there was a statistically significant negative correlation between cortisol concentrations and ligand affinity, which was not found in controls. Conclusion: Receptor down-regulation does not occur in PBML from patients with endogenous Cushing's syndrome. On the other hand, there seems to be a diminished ligand affinity which possibly reflects receptor modification in response to exposure to the continuously high cortisol levels in patients with Cushing's syndrome. This assumption is substantiated by the fact that in one patient a normalisation of the ligand affinity after complete remission of the disease was seen.

show abstract

Section: European Journal Of Endocrinology (2000) 142mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Huizenga¹,

Herder²,

Koper³

et al. 2000

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…A number of studies have shown that cellular sensitivity to glucocorticoids is influenced by glucocorticoid receptor density (Cidlowski & Cidlowski 1981, Vanderbilt et al 1987, Hoeck et al 1989, Silva et al 1994) with ligand-binding initiating a process of glucocorticoid receptor downregulation. This ligand-dependent receptor downregulation is mediated both at the level of gene transcription as well as protein stability (Svec & Rudis 1981, McIntyre & Samuels 1985, Dong et al 1988, Vedeckis et al 1989, Oakley & Cidlowski 1993).…”

Section: Introductionmentioning

confidence: 99%

UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation

Garside

Waters

Berry

et al. 2006

Journal of Endocrinology

View full text Add to dashboard Cite

Unlike other nuclear receptors, transactivation by the glucocorticoid receptor (GR) is increased by the inhibition of the ubiquitin/proteasome pathway. Here, we demonstrate that the ubiquitin-conjugating enzyme (E2), UbcH7, physically interacts with the GR and, when overexpressed, reduces the ability of the receptor to upregulate gene expression. Chemical inhibition of the 26S proteasome abolished the downregulation effect of overexpressed UbcH7, suggesting a role for the 26S proteasome, and GR protein stability in mediating the UbcH7 effect. Furthermore, a UbcH7 dominant negative mutant (C89S), unable to transfer ubiquitin, failed to repress GR transactivation. Indeed, overexpression of the mutant UbcH7 was sufficient to augment GR transactivation to levels achieved using the proteasome inhibitor MG132, but there was no further induction when MG132 and the UbcH7 mutant were used together. Expression of the dominant negative UbcH7 abolished ligand-dependent downregulation of GR protein, suggesting that the UbcH7 effect was mediated by regulation of GR protein concentration. Taken together, these data show that UbcH7 is a key regulator of GR turnover and glucocorticoid sensitivity.

show abstract

“…The cellular level of GR is dynamic and regulated in a cell-type specific manner by the surrounding concentration of the ligand (59). Administration of GR agonists results in downregulation of the GR (60,61) by the mechanisms that can be attributed to reduced transcription of the GR gene, as well as to decreased stability of the GR mRNA and protein (62). In contrast, hormone-induced upregulation of GR (autoinduction) is associated with glucocorticoid sensitivity.…”

Section: Glucocorticoid Receptor Expressionmentioning

confidence: 99%

Glucocorticoid Receptor in Health and Disease

Dunđerski¹,

Matić²

2009

Journal of Medical Biochemistry

View full text Add to dashboard Cite

Glucocorticoid Receptor in Health and DiseaseGlucocorticoid hormones are essential for life, have a vital place in the treatment of inflammatory and autoimmune diseases and are increasingly implicated in the pathogenesis of a number of common disorders. Their action is mediated by an intracellular receptor protein, the glucocorticoid receptor (GR), functioning as a ligand-inducible transcription factor. Multiple synthetic glucocorticoids are used as potent antiinflammatory and immunosuppressive agents, but their therapeutic usefulness is limited by a wide range and severity of side-effects. One of the most important pharmaceutical goals has been to design steroidal and non-steroidal GR ligands with profound therapeutic efficacy and reduced unwanted effects. The therapeutic benefit of glucocorticoid agonists is frequently compromised by resistance to glucocorticoids, which may depend on: access of the hormones to target cells, steroid metabolism, expression level and isoform composition of the GR protein, mutations and polymorphisms in the GR gene and association of the receptor with chaperone proteins. The major breakthrough into the critical role of glucocorticoid signaling in the maintenance of homeostasis and pathogenesis of diseases, as well as into the molecular mechanisms underlying the therapeutic usefulness of antiinflammatory drugs acting through the GR is expected to result from the current progress in large-scale gene expression profiling technologies and computational biology.

show abstract

Regulation of the human glucocorticoid receptor by long-term and chronic treatment with glucocorticoid

Cited by 118 publications

References 16 publications

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

Decreased ligand affinity rather than glucocorticoid receptor down-regulation in patients with endogenous Cushing's syndrome

UbcH7 interacts with the glucocorticoid receptor and mediates receptor autoregulation

Glucocorticoid Receptor in Health and Disease

Contact Info

Product

Resources

About