Glucocorticoid Hormone Receptors Research Articles

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer.

Androgen receptor (AR) antagonists play important roles in the treatment of castration-resistant prostate cancer (CRPC). The glucocorticoid receptor (GR) upregulation leads to drug resistance for clinically used antiandrogens. Therefore, blocking AR/GR signaling simultaneously has become an efficient strategy to overcome the drug resistance of CRPC. Our previous work indicated that Z19 could inhibit the activity of both AR and GR. Herein, we optimized the structure of Z19 and identified GA32 as a potent AR/GR dual inhibitor. GA32 efficiently reduced the mRNA and protein levels of AR/GR downstream genes. GA32 efficiently inhibited the proliferation of enzalutamide resistance CRPC both in vitro and in vivo. GA32 could directly bind to AR and GR, and the predicted binding modes for GA32 with AR/GR suggested that GA32 binds to the AR or GR hormone binding pocket. This work provides a potential lead compound with dual AR/GR inhibitory activity to conquer the drug resistance of CRPC.

Endocrine disrupting potential of total and bioaccessible extracts of dust from seven different types of indoor environment

Information on the indoor environment as a source of exposure with potential adverse health effects is mostly limited to a few pollutant groups and indoor types. This study provides a comprehensive toxicological profile of chemical mixtures associated with dust from various types of indoor environments, namely cars, houses, prefabricated apartments, kindergartens, offices, public spaces, and schools. Organic extracts of two different polarities and bioaccessible extracts mimicking the gastrointestinal conditions were prepared from two different particle size fractions of dust. These extracts were tested on a battery of human cell-based bioassays to assess endocrine disrupting potentials. Furthermore, 155 chemicals from different pollutant groups were measured and their relevance for the bioactivity was determined using concentration addition modelling. The exhaustive and bioaccessible extracts of dust from the different microenvironments interfered with aryl hydrocarbon receptor, estrogen, androgen, glucocorticoid, and thyroid hormone (TH) receptor signalling, and with TH transport. Noteably, bioaccessible extracts from offices and public spaces showed higher estrogenic effects than the organic solvent extracts. 114 of the 155 targeted chemicals were detectable, but the observed bioactivity could be only marginally explained by the detected chemicals. Diverse toxicity patterns across different microenvironments that people inhabit throughout their lifetime indicate potential health and developmental risks, especially for children. Limited data on the endocrine disrupting potency of relevant chemical classes, especially those deployed as replacements for legacy contaminants, requires further study.

Imbalanced glucocorticoid and mineralocorticoid stress hormone receptor function has sex-dependent and independent regulatory effects in the mouse hippocampus

Many stress-related neuropsychiatric disorders display pronounced sex differences in their frequency and clinical symptoms. Glucocorticoids are primary stress hormones that have been implicated in the development of these disorders but whether they contribute to the observed sex bias is poorly understood. Glucocorticoids signal through two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR). To elucidate the sex-specific and independent actions of glucocorticoids in the hippocampus, we developed knockout mice lacking hippocampal GR, MR, or both GR and MR. Mice deficient in hippocampal MR or both GR and MR showed an altered molecular phenotype of CA2 neurons and reduced anxiety-like behavior in both sexes, but altered stress adaptation behavior only in females and enhanced fear-motivated cue learning only in males. All three knockout mouse models displayed reduced sociability but only in male mice. Male and female mice deficient in both hippocampal GR and MR exhibited extensive neurodegeneration in the dentate gyrus. Global transcriptomic analysis revealed a marked expansion in the number of dysregulated genes in the hippocampus of female knockout mice compared to their male counterparts; however, the overall patterns of gene dysregulation were remarkably similar in both sexes. Within and across sex comparisons identified key GR and MR target genes and associated signaling pathways underlying the knockout phenotypes. These findings define major sex-dependent and independent effects of GR/MR imbalances on gene expression and functional profiles in the hippocampus and inform new strategies for treating men and women with stress-related neuropsychiatric disorders.

Unexpected Consequences of Noise-Induced Hearing Loss: Impaired Hippocampal Neurogenesis, Memory, and Stress.

Noise-induced hearing loss (NIHL), caused by direct damage to the cochlea, reduces the flow of auditory information to the central nervous system, depriving higher order structures, such as the hippocampus with vital sensory information needed to carry out complex, higher order functions. Although the hippocampus lies outside the classical auditory pathway, it nevertheless receives acoustic information that influence its activity. Here we review recent results that illustrate how NIHL and other types of cochlear hearing loss disrupt hippocampal function. The hippocampus, which continues to generate new neurons (neurogenesis) in adulthood, plays an important role in spatial navigation, memory, and emotion. The hippocampus, which contains place cells that respond when a subject enters a specific location in the environment, integrates information from multiple sensory systems, including the auditory system, to develop cognitive spatial maps to aid in navigation. Acute exposure to intense noise disrupts the place-specific firing patterns of hippocampal neurons, “spatially disorienting” the cells for days. More traumatic sound exposures that result in permanent NIHL chronically suppresses cell proliferation and neurogenesis in the hippocampus; these structural changes are associated with long-term spatial memory deficits. Hippocampal neurons, which contain numerous glucocorticoid hormone receptors, are part of a complex feedback network connected to the hypothalamic-pituitary (HPA) axis. Chronic exposure to intense intermittent noise results in prolonged stress which can cause a persistent increase in corticosterone, a rodent stress hormone known to suppress neurogenesis. In contrast, a single intense noise exposure sufficient to cause permanent hearing loss produces only a transient increase in corticosterone hormone. Although basal corticosterone levels return to normal after the noise exposure, glucocorticoid receptors (GRs) in the hippocampus remain chronically elevated. Thus, NIHL disrupts negative feedback from the hippocampus to the HPA axis which regulates the release of corticosterone. Preclinical studies suggest that the noise-induced changes in hippocampal place cells, neurogenesis, spatial memory, and glucocorticoid receptors may be ameliorated by therapeutic interventions that reduce oxidative stress and inflammation. These experimental results may provide new insights on why hearing loss is a risk factor for cognitive decline and suggest methods for preventing this decline.

Combinatorial actions of glucocorticoid and mineralocorticoid stress hormone receptors are required for preventing neurodegeneration of the mouse hippocampus

Chronic stress contributes to numerous human pathologies including cognition impairments and psychiatric disorders. Glucocorticoids are primary stress hormones that activate two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR), that are both highly expressed in the hippocampus. To investigate potential combinatorial actions of hippocampal GR and MR, we developed mice with conditional knockout of both GR and MR in the hippocampus and compared them to their single knockout counterparts. Mice lacking MR alone or both GR and MR in the hippocampus exhibited altered expression of multiple CA2-specific neuronal markers and enhanced cue-dependent learning in a conditioned fear test. Provocatively, in contrast to the single knockouts, mice depleted of both GR and MR showed profound neurodegeneration of the hippocampus. Neuronal death was increased and neurogenesis was reduced in the dentate gyrus of the double knockout mice. Global gene expression assays of the knockout mice revealed a synergistic increase in the number of dysregulated genes in the hippocampus lacking both GR and MR. This large cohort of genes reliant on both GR and MR for expression was strongly associated with cell death and cell proliferation pathways. GR/MR complexes were detected in CA1 and dentate gyrus neurons suggesting receptor heterodimers contribute to the joint actions of GR and MR. These findings reveal an obligate role for MR signaling in regulating the molecular phenotype of CA2 neurons and demonstrate that combinatorial actions of GR and MR are essential for preserving dentate gyrus neurons and maintaining hippocampal health.

Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region-specific manner.

Thyroid hormones regulate adult metabolism partly through actions on mitochondrial oxidative phosphorylation (OXPHOS). They also affect neurological development of the brain, but their role in cerebral OXPHOS before birth remains largely unknown, despite the increase in cerebral energy demand during the neonatal period. Thus, this study examined prepartum development of cerebral OXPHOS in hypothyroid fetal sheep. Using respirometry, Complex I (CI), Complex II (CII), and combined CI&CII OXPHOS capacity were measured in the fetal cerebellum and cortex at 128 and 142days of gestational age (dGA) after surgical thyroidectomy or sham operation at 105dGA (term ~145dGA). Mitochondrial electron transfer system (ETS) complexes, mRNA transcripts related to mitochondrial biogenesis and ATP production, and mitochondrial density were quantified using molecular techniques. Cerebral morphology was assessed by immunohistochemistry and stereology. In the cortex, hypothyroidism reduced CI-linked respiration and CI abundance at 128dGA and 142dGA, respectively, and caused upregulation of PGC1α (regulator of mitochondrial biogenesis) and thyroid hormone receptor β at 128dGA and 142dGA, respectively. In contrast, in the cerebellum, hypothyroidism reduced CI&II- and CII-linked respiration at 128dGA, with no significant effect on the ETS complexes. In addition, cerebellar glucocorticoid hormone receptor and adenine nucleotide translocase (ANT1) were downregulated at 128dGA and 142dGA, respectively. These alterations in mitochondrial function were accompanied by reduced myelination. The findings demonstrate the importance of thyroid hormones in the prepartum maturation of cerebral mitochondria and have implications for the etiology and treatment of the neurodevelopmental abnormalities associated with human prematurity and congenital hypothyroidism.

A computational insight into endocrine disruption by polychlorinated biphenyls via non-covalent interactions with human nuclear receptors

Production of polychlorinated biphenyls (PCBs) was banned a long time ago because of their harmful health effects but humans continue to be exposed to residual PCBs in the environment. In this study, the susceptibility of human nuclear receptors to binding by PCBs was investigated using molecular docking simulation. Findings revealed that PCBs belonging to ortho-substituted, mono-ortho-substituted and non-ortho-substituted congeners could bind to agonistic conformations of androgen (AR), estrogen (ER α and ER β), glucocorticoid (GR) and thyroid hormone (TR α and TR β) receptors as well as antagonistic conformation of androgen receptor (AR an) but only ortho-substituted and mono-ortho-substituted PCBs could bind to estrogen receptors in their antagonistic conformations (ER α an and ER β an). Further molecular docking analyses showed that PCBs mimic the modes of interaction observed for the co-crystallized ligands in the crystal structures of the affected receptors, utilizing 81%, 83%, 78%, 60%, 75%, 60%, 86%, 100% and 75% of the amino acid residues utilized by the co-crystallized ligands for binding in AR, AR an, ER α, ER α an, ER β, ER β an, GR, TR α and TR β respectively. This computational study suggests that PCBs may cause endocrine disruption via formation of non-covalent interactions with androgen, estrogen, glucocorticoid and thyroid hormone receptors.

Theoretical study on endocrine disrupting effects of polychlorinated dibenzo-p-dioxins using molecular docking simulation.

Polychlorinated dibenzo-p-dioxins (PCDDs) are hypothesized to exert their toxic effects in wildlife and humans via endocrine disruption. However, very scanty information is available on the underlying molecular interactions that trigger this disruption. In this study, molecular docking simulation was used to predict the susceptibility of 12 nuclear receptors to disruption via PCDD bindings. Findings revealed that androgen (AR and AR an), estrogen (ER α and ER β), glucocorticoid (GR) and thyroid hormone (TR α and TR β) receptors are the most probable protein targets that bind to PCDDs. Further molecular docking analyses showed that PCDD molecules mimic the modes of interaction observed for the co-crystallized ligands of the affected receptors, resulting in the formation of ligand-receptor complexes that were stabilized through electrostatic, van der Waals, pi-effect and hydrophobic interactions with 18, 17, 17, 16, 18, eight and four amino acid residues in the active sites of AR, AR an, ER α, ER β, GR, TR α and TR β respectively. The commonalities of these interacting amino acid residues with those utilized by dihydrotestosterone in AR, bicalutamide in AR an, 17β-estradiol in ER α, 17β-estradiol in ER β, cortisol in GR, thyromimetic GC-1 in TR α and thyromimetic GC-1 in TR β are 86%, 74%, 94%, 80%, 82%, 50% and 43% respectively. The results obtained in this study provide supporting evidence that PCDD molecules may interfere with the endocrine system via binding interactions with some vital amino acid residues in the binding pockets of AR, ERs, GRs and TRs.

Effect-Directed Analysis of Progestogens and Glucocorticoids at Trace Concentrations in River Water.

Effect-based monitoring is increasingly applied to detect and-in conjunction with chemical analysis-to identify endocrine-disrupting compounds (EDCs) in the environment. Although this approach of effect-directed analysis has been successfully demonstrated for estrogenicity and androgenicity, data on progestogens and glucocorticoids driving endocrine disruption are quite limited. We investigated progestogenic and glucocorticoid activities in Danube River water receiving untreated wastewater from Novi Sad, Serbia. After a 2-step fractionation, all fractions were tested with reporter gene bioassays for agonistic and antagonistic hormonal responses at progestogenic and glucocorticoid hormone receptors as well as with target and nontarget analytical screening of active fractions by liquid chromatography-high-resolution mass spectrometry. Due to masking by cytotoxic mixture components, the effects could not be detected in the raw water extract but were unraveled only after fractionation. Target chemical screening of the fraction that was active in the progesterone receptor (PR) assay revealed that progesterone and megestrol acetate were predominant drivers of PR-mediated activity along with medroxyprogesterone, dihydrotestosterone, androsterone, and epiandrosterone. Hydrocortisone was detected at sub-ng/L concentration in the active fraction in the glucocorticoid receptor (GR) assay but could not explain a significant fraction of the observed GR activity. The present study indicates that effect-based monitoring is a powerful tool to detect EDCs in the aquatic environment but that fractionation may be required to avoid masking effects of mixture components. Future effect-directed analysis studies are required to better understand the occurrence of EDCs and masking compounds in different lipophilicity windows, to finally reduce fractionation requirements for monitoring to a smart clean-up. Environ Toxicol Chem 2019;39:189-199. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Continuous Free Cortisol Profiles in Healthy Men.

In humans, approximately 95% of circulating cortisol is bound to corticosteroid-binding globulin and albumin. It is only the free fraction that is biologically active and can activate signaling pathways via glucocorticoid hormone receptors in cells. Microdialysis is a well-established technique that enables the sampling of molecules in different compartments of the body, including extracellular fluid. This is the first study validating a rapid sampling microdialysis method measuring free cortisol in the subcutaneous and blood compartments of healthy volunteers. Healthy nonsmoking volunteers (42 men, aged 18-24 years; body mass index 18-25 kg/m2) received placebo (saline), 250 μg Synacthen, or 1 mg dexamethasone with 10-minute sampling to measure total and free cortisol (subcutaneous, intravenous, and saliva) for an hour before and 4 hours after administration. Following stimulation by Synacthen, total serum cortisol and free cortisol in both compartments rose significantly, achieving and maintaining maximum levels between 2 and 3 hours following the stimulus. A decline in cortisol levels was evident after the administration of dexamethasone or placebo, but there was a clear pulsatile activity around lunchtime in the latter group, which was prominent in the blood compartment (total and free cortisol). There was good correlation between serum total and free cortisol (subcutaneous and intravenous) in the Synacthen and dexamethasone groups with no significant delay (less than 5 minutes) between total and free cortisol. This seminal study demonstrated the dynamic responses of total blood cortisol and microdialysis derived free cortisol in blood, subcutaneous tissue, and saliva in men.

Ginseng on Nuclear Hormone Receptors.

The first record of ginseng use dates back over two millennia, and ginseng is now popular in more than 35 countries. Ginsenosides are the pharmacological constituents responsible for the beneficial effects of ginseng. There is increasing evidence that ginseng and its bioactive ingredients are involved in the regulation of nuclear receptors, molecules that act in response to the specific binding of hormones, which link to a diverse array of signaling pathways, such as the ERK and PI3K/Akt pathways. Knowledge of the mechanism of how ginseng mediates these complexes is essential for the development of multi-target phytomedicine as possible therapy for different diseases. Here, we discuss the literature on the effects of ginseng and its constituents on estrogen, glucocorticoid, peroxisome proliferator-activated, and androgen nuclear hormone receptors, as well as how ginseng and its constituents exert their biological function in the treatment of cancer, obesity, and cardiovascular and neurological disorders. The accumulated results definitely show that the nuclear receptors are cellular targets of ginsenosides, but more rigorous data are required to establish and provide a scientific basis to confirm the suggested efficacy of ginseng or products with ginsenosides.

Abstract 5040: Genomic and proteomic characterization of anti-androgen resistant cell lines

Abstract Background: Prostate cancer is the most common cancer and second most frequent cause of cancer-related deaths for men in the United States. AR-axis inhibitors have been shown to improve both progression-free survival (PFS) and overall survival (OS) in castration resistant prostate cancer (CRPC) patients however an estimated 50% of patients will go on to develop resistance to these therapies. Some mechanisms of resistance observed in the clinic include Androgen Receptor (AR) dependent events such as increased AR copy number, activating point mutations in AR, or splice variants (ARV7) both of the latter leading to constitutively active versions of AR. Alternatively, AR-independent resistance mechanisms include up-regulation of other oncogenic signaling pathways such as FGFR and PI3/Akt and induction of the nuclear hormone Glucocorticoid Receptor (GR). Finally, an increase in the emergence of a neuroendocrine phenotype is observed in the clinic with CRPC patients and is thought to be associated with chronic AR-antagonist treatment. To better understand the specific proteomic and genomic changes that occur during chronic AR inhibitor treatment we developed two enzalutamide (ENZA) resistant cell lines and performed targeted proteomic and global gene expression analysis. Methods: We generated LnCaP and VCAP ENZA-resistant (ENZA-Res) prostate cancer cell lines. We performed gene expression analysis by using both cDNA microarray and RNA-SEQ techniques to identify novel or differential gene expression patterns between ENZA-Res and sensitive phenotypes. We also employed a targeted proteomic approach to identify changes in the relative expression levels of proteins that have historically been associated with anti-androgen resistance including, ARV7, GR and SGK-1. Results: We have shown that ENZA-Res cell lines can undergo a significant change in morphology that is associated with an elongated neuronal-like appearance. This phenotype is associated with an induction in the mRNA expression of neuroendocrine markers, CHGA and REST along with a strong induction of GR mRNA and protein expression. We have shown that the neuroendocrine derived prostate cancer cell line, H660, also demonstrates high GR mRNA and protein content suggesting that GR may have a role in the maintenance of neuroendocrine and/ or ENZA-Res phenotypes when AR is absent. In VCaP ENZA-Res cells a significant increase in ARV7 mRNA and protein content was observed compared to parental ENZA sensitive VCaP cells. Lastly, we employed a combination of cDNA microarray and RNA-SEQ techniques to identify a molecular signature associated with anti-androgen resistance. We have identified a unique subset of genes that are differentially up-regulated in ENZA-Res cell lines compared to ENZA-sensitive cell lines. This novel molecular signature identifies several candidate genes as potential therapeutic targets that may be important in mediating anti-androgen resistance. Citation Format: Jennifer Hertzog, Mike Russell, Michael Quigley, Marco Gottardis, Theresa McDevitt. Genomic and proteomic characterization of anti-androgen resistant cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5040.

Prevention effect of rare ginsenosides against stress-hormone induced MTOC amplification.

Stress has been suggested as one of important cause of human cancer without molecular biological evidence. Thus, we test the effect of stress-related hormones on cell viability and mitotic fidelity. Similarly to estrogen, stress hormone cortisol and its relative cortisone increase microtubule organizing center (MTOC) number through elevated expression of γ-tubulin and provide the Taxol resistance to human cancer cell lines. However, these effects are achieved by glucocorticoid hormone receptor (GR) but not by estrogen receptor (ER). Since ginsenosides possess steroid-like structure, we hypothesized that it would block the stress or estrogen-induced MTOC amplification and Taxol resistance. Among tested chemicals, rare ginsenoside, CSH1 (Rg6) shows obvious effect on inhibition of MTOC amplification, γ-tubulin induction and Taxol resistance. Comparing to Fulvestant (FST), ER-α specific inhibitor, this chemical can block the cortisol/cortisone-induced MTOC deregulation as well as ER-α signaling. Our results suggest that stress hormone induced tumorigenesis would be achieved by MTOC amplification, and CSH1 would be useful for prevention of stress-hormone or steroid hormone-induced chromosomal instability.

Endocrine disrupting activities of surface water associated with a West Virginia oil and gas industry wastewater disposal site

Currently, >95% of end disposal of hydraulic fracturing wastewater from unconventional oil and gas operations in the US occurs via injection wells. Key data gaps exist in understanding the potential impact of underground injection on surface water quality and environmental health. The goal of this study was to assess endocrine disrupting activity in surface water at a West Virginia injection well disposal site. Water samples were collected from a background site in the area and upstream, on, and downstream of the disposal facility. Samples were solid-phase extracted, and extracts assessed for agonist and antagonist hormonal activities for five hormone receptors in mammalian and yeast reporter gene assays. Compared to reference water extracts upstream and distal to the disposal well, samples collected adjacent and downstream exhibited considerably higher antagonist activity for the estrogen, androgen, progesterone, glucocorticoid and thyroid hormone receptors. In contrast, low levels of agonist activity were measured in upstream/distal sites, and were inhibited or absent at downstream sites with significant antagonism. Concurrent analyses by partner laboratories (published separately) describe the analytical and geochemical profiling of the water; elevated conductivity as well as high sodium, chloride, strontium, and barium concentrations indicate impacts due to handling of unconventional oil and gas wastewater. Notably, antagonist activities in downstream samples were at equivalent authentic standard concentrations known to disrupt reproduction and/or development in aquatic animals. Given the widespread use of injection wells for end-disposal of hydraulic fracturing wastewater, these data raise concerns for human and animal health nearby.

Nuclear Transcription Factors in the Mitochondria: A New Paradigm in Fine-Tuning Mitochondrial Metabolism.

Noncanonical functions of several nuclear transcription factors in the mitochondria have been gaining exceptional traction over the years. These transcription factors include nuclear hormone receptors like estrogen, glucocorticoid, and thyroid hormone receptors: p53, IRF3, STAT3, STAT5, CREB, NF-kB, and MEF-2D. Mitochondria-localized nuclear transcription factors regulate mitochondrial processes like apoptosis, respiration and mitochondrial transcription albeit being nuclear in origin and having nuclear functions. Hence, the cell permits these multi-stationed transcription factors to orchestrate and fine-tune cellular metabolism at various levels of operation. Despite their ubiquitous distribution in different subcompartments of mitochondria, their targeting mechanism is poorly understood. Here, we review the current status of mitochondria-localized transcription factors and discuss the possible targeting mechanism besides the functional interplay between these factors.

Dietary fructose-related adiposity and glucocorticoid receptor function in visceral adipose tissue of female rats

Excessive fructose intake coincides with the growing rate of obesity and metabolic syndrome, with women being more prone to these disorders than men. Findings that detrimental effects of fructose might be mediated by glucocorticoid regeneration in adipose tissue only indirectly implicated glucocorticoid receptor (GR) in the phenomenon. The aim of the present study was to elucidate whether fructose overconsumption induces derangements in GR expression and function that might be associated with fructose-induced adiposity in females. We examined effects of fructose-enriched diet on GR expression and function in visceral adipose tissue of female rats. Additionally, we analyzed the expression of genes involved in glucocorticoid prereceptor metabolism [11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase], lipolysis (hormone-sensitive lipase) and lipogenesis (sterol regulatory element binding protein 1 and peroxisomal proliferator-activated receptor γ). Fructose-fed rats had elevated energy intake that resulted in visceral adiposity, as indicated by increased visceral adipose tissue mass and its share in the whole-body weight. GR hormone binding capacity and affinity, as well as the expression of GR gene at both mRNA and protein levels were reduced in visceral adipose tissue of the rats on fructose diet. The glucocorticoid prereceptor metabolism was stimulated, as evidenced by elevated tissue corticosterone, while the key regulators of lipolysis and lipogenesis remained unaffected by fructose diet. The results suggest that the 11βHSD1-mediated elevation of intracellular corticosterone may induce GR downregulation, which may be associated with failure of GR to stimulate lipolysis in fructose-fed female rats.

Final steps in the feedback regulation of human glucocorticoid receptor gene and role of nuclear protein phosphatase 2A

Abstract The feedback regulation of the human glucocorticoid receptor gene by glucocorticoid receptor-hormone complexes involves the recruitment of the nuclear phosphatase, PP2A. The PP2A holoenzyme consists of a structural subunit A, a

Coexistence of Glucocorticoid Resistance and Pseudohypoparathyroidism

We report for the first time the case of a young man who developed both glucocorticoid resistance and resistance to parathyroid hormone. Treatment with high doses of dexamethasone together with administration of calcium and calcitriol resulted in a significant improvement in the patients condition. In this paper, we discuss in detail diagnostic and treatment strategies used on the patient and the impact on the course and outcome of both disorders. We associate the development of both these disorders with a possible inherited defect in the signal pathways common to glucocorticoid and parathyroid hormone receptors.

Glucocorticoid receptor isoforms generated by alternative splicing and alternative translation initiation

The glucocorticoid hormone receptor (NR3C1) is the transcription factor that controls a large variety of physiological processes in mammals. According to modern estimates, the glucocorticoid receptor participates in regulation of the expression of thousands of genes; however, the sets of glucocorticoid-controlled genes in different cell types are different. At the same time the amplitude, directivity, and time- and dose-dependence of the hormone response are broadly variable both for the same gene in different cell types and for different genes in the same cell. Such specificity of a glucocorticoid receptor is determined, on the one hand, by architecture of regulatory regions of target genes, and on the other hand, by the complexity of the glucocorticoid receptor gene. The gene has nine alternative promoters and produces numerous protein isoforms as a result of alternative splicing and alternative translation initiation. This review summarizes the current knowledge on glucocorticoids receptor isoforms and mechanisms of their formation.

Defective glucocorticoid hormone receptor signaling leads to increased stress and anxiety in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder caused due to deletions or loss-of-function mutations in maternally inherited UBE3A. Ube3a functions as an ubiquitin ligase as well as a transcriptional coactivator of steroid hormone receptors. However, the mechanisms by which maternal Ube3a deficiency gives rise to phenotypic features of AS are not clear. We report here that Ube3a regulates glucocorticoid receptor (GR) transactivation and GR signaling pathway is disrupted in Ube3a-maternal-deficient mice brain. The expression of several GR-dependent genes is down-regulated in multiple brain regions of Ube3a-maternal-deficient mice. AS mice show significantly higher level of blood corticosterone, selective loss of GR and reduced number of parvalbumin-positive inhibitory interneurons in their hippocampus that could ultimately lead to increased stress. These mice also exhibit increased anxiety-like behavior, which could be due to chronic stress. Altogether, our findings suggest that chronic stress due to altered GR signaling might lead to anxiety-like behavior in a mouse of model of AS.