Residues in the Ligand Binding Domain That Confer Progestin or Glucocorticoid Specificity and Modulate the Receptor Transactivation Capacity

Robin-Jagerschmidt, Catherine; Wurtz, Jean‐Marie; Guillot, Benoı̂t; Gofflo, Dominique; Benhamou, Brigitte; Vergezac, Agnès; Ossart, Christèle; Moras, Dino; Philibert, D.

doi:10.1210/mend.14.7.0484

Cited by 22 publications

(14 citation statements)

References 26 publications

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“…Nuclear receptor LBDs conform to a canonical folding architecture (46). The model of the hGR␣ presented here is similar to previously published homology models of the GR LBD also generated from the structure of the progesterone receptor LBD (33,34). In addition, comparison of our model with the solved structure (M. Lambert, personal communication) supports the claim that the hGR␣ model presented here is a valid model and is sufficiently similar to the experimental structure to support our conclusions.…”

Section: Discussionsupporting

confidence: 87%

Molecular Origins for the Dominant Negative Function of Human Glucocorticoid Receptor Beta

Yudt

Jewell²,

Bienstock

et al. 2003

Molecular and Cellular Biology

149

114

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This study molecularly elucidates the basis for the dominant negative mechanism of the glucocorticoid receptor (GR) isoform hGR␤, whose overexpression is associated with human glucocorticoid resistance. Using a series of truncated hGR␣ mutants and sequential mutagenesis to generate a series of hGR␣/␤ hybrids, we find that the absence of helix 12 is neither necessary nor sufficient for the GR dominant negative phenotype. Moreover, we have localized the dominant negative activity of hGR␤ to two residues and found that nuclear localization, in addition to heterodimerization, is a critical feature of the dominant negative activity. Molecular modeling of wild-type and mutant hGR␣ and hGR␤ provides structural insight and a potential physical explanation for the lack of hormone binding and the dominant negative actions of hGR␤.Glucocorticoids are among the most widely used classes of drugs in the world. The anti-inflammatory effects of glucocorticoids are routinely exploited in treatment of many pathological conditions ranging from asthma, rheumatoid arthritis, ulcerative colitis, and common eczema. Likewise, the immunosuppressive benefits of glucocorticoids afford them a role in most chemotherapeutic regimes as well as for management of autoimmunity. However, prolonged glucocorticoid treatment, as well as rare genetic dispositions, can result in glucocorticoid resistance (7). An increasing number of studies in the last several years have implicated alternative splicing of the glucocorticoid receptor (GR) gene and subsequent expression of the hGR␤ protein isoform as a contributing factor to glucocorticoid resistance in a variety of pathological conditions (17,21,28,38,39,41). Since hGR␤ does not undergo ligand-induced down regulation and has an increased half-life, the expression of hGR␤ becomes more significant (31). Expression of hGR␤ is also enhanced by proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin 1; however, a precise physiological role for hGR␤ remains elusive (43).The GR, a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, participates in numerous signaling pathways leading to altered gene expression in target cells and tissues and is essential for life (8). The GR can modulate gene expression either positively or negatively by directly binding as a homodimer to glucocorticoid response elements (GRE) located in the promoter regions of target genes. Alternatively, the ligand-activated GR is known to repress or antagonize other nuclear factors involved in regulating gene expression, such as NF-B and AP-1, through direct protein interactions (29). Both of these functions of GR signaling and transactivation and transrepression, appear to involve distinct and separable regions of the receptor and are major components of the physiological response to both natural and synthetic glucocorticoids.In humans, alternative splicing of the ninth and final GR exon gives rise to hGR␣ and hGR␤ proteins divergent at only the extreme carboxy termini (11,20...

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Section: Discussionsupporting

confidence: 87%

Molecular Origins for the Dominant Negative Function of Human Glucocorticoid Receptor Beta

Yudt

Jewell²,

Bienstock

et al. 2003

Molecular and Cellular Biology

149

114

View full text Add to dashboard Cite

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“…Ligand-activated GRs act as transcription factors that regulate the expression of target genes by binding to specific DNA sequences in their promoter region (Robin-Jagerschmidt et al 2000;Kellendonk et al 2002). We found that the conditional inactivation of brain GRs attenuated PER2 rhythms in the BNSTov and CEA in the mouse (Segall et al 2009).…”

Section: Introductionmentioning

confidence: 73%

Exogenous Corticosterone Induces the Expression of the Clock Protein, PERIOD2, in the Oval Nucleus of the Bed Nucleus of the Stria Terminalis and the Central Nucleus of the Amygdala of Adrenalectomized and Intact Rats

Segall

Amir

2010

J Mol Neurosci

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The cyclical expression of the clock protein PERIOD2 (PER2) in select regions of the limbic forebrain is contingent upon the rhythmic secretion of the adrenal glucocorticoid, corticosterone. Daily rhythmic PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and the central nucleus of the amygdala (CEA) is abolished with the removal of the adrenal glands but restored with rhythmic hormone replacement via the drinking water at a time corresponding to the endogenous peak of circulating glucocorticoids. Here, we investigated the effects of serial or acute systemic injections of corticosterone on the expression of PER2 in the BNSTov and CEA of both adrenalectomized (ADX) and intact rats. We sought to determine whether there is a temporal window of corticosterone sensitivity by delivering the hormone at a time corresponding to trough levels of circulating glucocorticoids, at lights on. We found that daily morning injections of corticosterone induced PER2 expression in the BNSTov and CEA of ADX rats, with levels peaking 1 h after injection. In intact rats, daily morning injections significantly upregulated the expression of PER2 in the BNSTov and CEA 1 h after injection and dampened the evening peak, while a single injection abolished the rhythm of PER2 expression in the CEA but had no effect on PER2 in the BNSTov. Our findings suggest that despite the potential masking effect of signals from the light-entrained master clock, daytime chronic and acute corticosterone administration can alter the rhythmic expression of PER2 in the BNSTov and CEA, and that the response is region-specific and dependent on the duration of treatment.

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“…There are precedents for this type of effect in other steroid hormone receptors. The specificity of dexamethasone binding to the GR involves two residues, Asp 641 and Leu 647 (Robin-Jagerschmidt et al 2000), that do not interact directly with the ligand in the GR LBD crystal structure (Bledsoe et al 2002). Similarly, the binding of the progestin RU27987 to the PR is conferred, in part, by a serine residue that lies on the surface of the receptor (RobinJagerschmidt et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Determinants of spironolactone binding specificity in the mineralocorticoid receptor

Rogerson¹,

Yao²,

Smith³

et al. 2003

Journal of Molecular Endocrinology

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Spironolactone is a mineralocorticoid receptor (MR) antagonist in clinical use. The compound has a very low affinity for the glucocorticoid receptor (GR). Determinants of binding specificity of spironolactone to the MR were investigated using chimeras created between the ligand-binding domains (LBDs) of the MR and the GR. These chimeras had previously been used to investigate aldosterone binding specificity to the MR. Spironolactone was able to compete strongly for [3 H]-aldosterone and [ 3 H]-dexamethasone binding to a chimera containing amino acids 804-874 of the MR, and weakly for [ 3 H]-dexamethasone binding to a chimera containing amino acids 672-803 of the MR. Amino acids 804-874 were also critical for aldosterone binding specificity. Models of the MR LBD bound to aldosterone and spironolactone were created based on the crystal structure of the progesterone receptor LBD. The ligand-binding pocket of the MR LBD model consisted of 23 amino acids and was predominantly hydrophobic in nature. Analysis of this model in light of the experimental data suggested that spironolactone binding specificity is not governed by amino acids in the ligand-binding pocket.

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Residues in the Ligand Binding Domain That Confer Progestin or Glucocorticoid Specificity and Modulate the Receptor Transactivation Capacity

Cited by 22 publications

References 26 publications

Molecular Origins for the Dominant Negative Function of Human Glucocorticoid Receptor Beta

Molecular Origins for the Dominant Negative Function of Human Glucocorticoid Receptor Beta

Exogenous Corticosterone Induces the Expression of the Clock Protein, PERIOD2, in the Oval Nucleus of the Bed Nucleus of the Stria Terminalis and the Central Nucleus of the Amygdala of Adrenalectomized and Intact Rats

Determinants of spironolactone binding specificity in the mineralocorticoid receptor

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