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At least 19 recordsLinked to original sources
PubMed2005

Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha.

Cytochrome P450 (P450) enzymes play important roles in the metabolism of endogenous and xenobiotic substrates in humans. CYP2C8 is an important member of the CYP2C subfamily, which metabolizes both endogenous compounds (i.e., arachidonic acids and retinoic acid) and xenobiotics (e.g., paclitaxel). Induction of P450 enzymes by drugs can result in tolerance as well as drug-drug interactions. CYP2C8 is the most strongly inducible member of the CYP2C subfamily in human hepatocytes, but the mechanism of induction by xenobiotics has not been delineated. To determine the mechanisms controlling the regulation of this important P450, we cloned the 5'-flanking region of CYP2C8 and investigated its transcriptional regulation by nuclear factors such as the pregnane X receptor (PXR), constitutive androstane receptor (CAR), glucocorticoid receptor (GR), and hepatic nuclear factor 4 (HNF4alpha) that are known to be involved in the induction of other P450 enzymes using both cell lines and primary hepatocyte models. We initially identified a distal PXR/CAR-binding site in the CYP2C8 promoter that confers inducibility of CYP2C8 via the PXR agonist/ligand rifampicin and the CAR agonist/ligand CITCO [6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime]. A glucocorticoid-responsive element was identified that mediates dexamethasone induction via the GR. We finally identified an HNF4alpha-binding site within the CYP2C8 basal promoter region that is cis-activated by cotransfected HNF4alpha. In summary, the present studies show that CAR, PXR, GR, and HNF4alpha can regulate CYP2C8 expression and identify specific cis-elements within the promoter that control these regulatory pathways.

Androstanes↗
PubMed1983

Distribution of thyroid hormone receptors, glucocorticoid receptors, and growth hormone gene sequences in chromatin from cultured rat pituitary cells.

Chromatin from rat pituitary tumor (GH3) cells was fractionated into transcriptionally active and inactive domains. When the various chromatin fractions were assayed for their content of growth hormone gene sequences, it was found that these sequences were highly enriched in those chromatin fractions most sensitive to micrococcal nuclease. Fraction S1 showed the highest enrichment in growth hormone genes and was impoverished in histones H3 and H4. The distribution of specifically bound thyroid and glucocorticoid receptors in chromatin fractions enriched and depleted in growth hormone gene sequences was also examined. Both thyroid and glucocorticoid receptors are enriched to different extents in transcriptionally active chromatin. Within active chromatin, both types of receptors exist in more than one molecular form.

Animals↗
PubMed1994

Heat shock protein is tightly associated with the recombinant human glucocorticoid receptor:glucocorticoid response element complex.

The association of heat shock proteins (hsp) with steroid hormone receptors may have functional significance for steroid receptor action. The association of hsp90 with steroid receptors is thought to maintain the receptors in the nonactivated state until their interaction with the respective ligand. The association of hsp70 with progesterone receptor has been well documented. However, there is evidence both for and against the association of hsp70 with the glucocorticoid receptor (GR). We have examined the interaction between hsp70 and human (h) GR over-expressed in the Baculovirus system. Immunoprecipitation and sucrose gradient centrifugation studies demonstrated the association of hsp70 with both the nonactivated and in vitro activated hGR. We were unable to dissociate hGR and hsp70 by incubation of crude cytosol with 3 mM ATP and 0.5 M NaCl. In vivo activation of hGR did not result in dissociation of hsp70 from hGR. Hsp70 coeluted with hGR from a glucocorticoid response element (GRE)-Sepharose column, suggesting that hsp70 is part of the GRE-hGR complex. Both an anti-hGR antibody and an anti-hsp70 antibody were capable of further retarding the migration of a [32P]GRE-hGR complex in polyacrylamide gels. The in vitro activated hGR has been shown to be highly active in an in vitro transcription system. We speculate that hsp70 may influence the DNA-binding and/or transcriptional activities of hGR.

Base Sequence↗
PubMed1987

Characterization of glucocorticoid receptors and glucocorticoid receptor mRNA in human leukemia cells: stabilization of the receptor by diisopropylfluorophosphate.

We have shown that cytosol samples from human leukemia cells frequently contain glucocorticoid receptor fragments that have a mol wt (Mr) of approximately 52,000. In the present study we demonstrate that the Mr approximately 52,000-receptor fragments are derived from intact glucocorticoid receptors (Mr approximately 97,000) by the action of a serine protease. Mr approximately 52,000-receptor fragments were present in cytosol from 24 of 52 leukemia cell samples. Only normal size glucocorticoid receptors were present in cytosol samples if diisopropylfluorophosphate (DFP), a potent inhibitor of serine proteases, was added to the hypotonic buffer used for cytosol preparation. Receptor proteolysis was not inhibited by hydrolyzed DFP, benzamidine, phenylmethylsulfonylfluoride, aprotinin, iodoacetamide, or mercuric chloride. The leukemia cell protease digests the receptor at a different site than chymotrypsin, which digests the intact receptor to produce a Mr approximately 40,000 receptor fragment. Receptor messenger RNA (mRNA) in S49 mouse lymphoma cells and in human leukemia cells was analyzed by Northern hybridization with a cDNA for the normal glucocorticoid receptor. Mutant S49 mouse lymphoma cells that have abnormally small glucocorticoid receptors (Mr approximately 48,000) make a 5.0-kilobase receptor transcript in addition to the normal size 6.5-kilobase receptor transcript. A normal size receptor transcript of 6.5 kilobases was present in all of the human leukemia cells whether or not Mr approximately 52,000-receptor fragments were present. Therefore, abnormalities of glucocorticoid receptor mRNA, which may give rise to the synthesis of foreshortened receptors in certain mutant mouse lymphoma cells, are apparently absent from human leukemia cells.

Animals↗
PubMed1993

Localization of glucocorticoid receptors and glucocorticoid receptor mRNAs in the rat cochlea.

The distribution of glucocorticoid (GR) receptor messenger RNAs (mRNAs) and GR receptors was studied by in situ hybridization histochemistry and immunocytochemistry, respectively. In situ hybridization histochemistry was performed with a biotin-labeled riboprobe complementary to rat GR receptor mRNA. GR receptor mRNAs were demonstrated in spiral ligament cells, spiral limbus cells, and spiral ganglion cells. GR receptor mRNAs were demonstrated neither in cells of the stria vascularis nor in cells of the organ of Corti region. With the use of a monoclonal and a polyclonal antibody, GR receptors were observed in the spiral ligament cells, stria vascularis cells, spiral limbus cells, and spiral ganglion cells by immunocytochemistry. Binding of anti-GR-receptor antibodies to a lesser extent was observed in the organ of Corti region; however, cellular distribution of the GR receptors could not be resolved with the applied techniques. These results suggest that the GR receptor is expressed differently in the heterogeneous cochlear tissues.

Animals↗
PubMed1992

Glucocorticoid receptors.

Glucocorticoid hormones are secreted uniquely from the zona fasciculata of the adrenal cortex, with marked circadian variation in basal levels and acute elevation in response to stress. Glucocorticoid receptors are almost ubiquitously distributed, and mediate a wide range of tissue-specific responses; in addition to classical, [3H]dexamethasone-binding GR (Type II receptors) there is excellent evidence that Type I sites (MR) act as mineralocorticoid receptors in some tissues but high affinity glucocorticoid receptors in others. Particular issues to be addressed in the presentation include: (i) the extent to which glucocorticoid receptor occupancy is modulated by extracellular (plasma-binding enzymes) or intracellular (proto-oncogenes) factors; (ii) whether or not there are specific response elements for Type I and II receptors; (iii) putative physiological roles for Type I, high affinity glucocorticoid receptors; (iv) evidence for glucocorticoid receptors other than classical GR and "MR". In summary, glucocorticoid receptors appear to be a final common pathway mediating and/or modulating circadian rhythms and stress responses. Cell-and tissue-specificity of response to a whole-body signal is determined by local pre-receptor, receptor and genomic differences. On the basis of previous studies on glucocorticoid secretion, and recent information on glucocorticoid action, it would at last appear possible to begin to construct a coherent physiology for glucocorticoid hormones.

Animals↗
PubMed1994

Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor.

Glucocorticoids, which are widely used as antiinflammatory agents, downregulate the expression of the interleukin 6 gene and of additional cytokine genes involved in inflammatory responses. Conversely, the transcription factor NF-kappa B, a member of the Rel family of transcription factors, has been implicated in the induction of multiple genes involved in the early processes of immune and inflammatory responses. This prompted us to investigate whether one of the mechanisms by which glucocorticoids exert their antiinflammatory activities is through inhibition of gene activation mediated by NF-kappa B. We report that, in intact cells, activation of the interleukin 6 promoter by a combination of the factor NF-IL6 and the p65 subunit of NF-kappa B is inhibited by dexamethasone (ligand)-activated glucocorticoid receptor. Conversely, activation of the mouse mammary tumor virus promoter by a combination of dexamethasone and glucocorticoid receptor is inhibited by overexpression of p65. Furthermore, we provide evidence for physical association between glucocorticoid receptor and p65 in protein crosslinking and coimmunoprecipitation experiments, using either in vitro translated proteins or those present in cell extracts. These studies suggest that direct interactions between NF-kappa B and glucocorticoid receptor may partly account for the antiinflammatory properties of glucocorticoids in vivo.

Base Sequence↗
PubMed1979

Glucocorticoid receptors.

Glucocorticoid receptors are found in most mammalian tissues and have been studied in detail in a number of tissue culture systems. With cells that have not been exposed to steroids, the receptors are found in the cytoplasmic fraction from which they can be isolated and studied. Methods for studying glucocorticoid receptors depend on their high-affinity specific binding of radioactive steroids. The reversible interaction is intracellular. It follows Michaelian kinetics, at least in cell-free cytosol, and involves a thermodynamically homogeneous population of about 10 000 sites per cell. The receptor is an asymmetric, slightly acidic protein of about 100 000 daltons. It is very labile, especially in the unbound form. Binding activity depends on the integrity of thiol groups and perhaps on phosphorylation of amino acid residues. Although indirect, the evidence is overwhelmingly convincing that this protein is the physiologic glucocorticoid receptor. The time-kinetics of binding and dissociation are consistent with the sequence of events in glucocorticoid action. Various steroid analogs display binding characteristics predictable from their glucocorticoid activity. Loss of the binding protein from certain cultured cell lines is accompanied by unresponsiveness to glucocorticoids. The extensive tissue distribution of receptors parallels the extensive role of glucocorticoids in regulation. Finally, there is a strong correlation between nuclear binding of receptors and nuclear effects of the steroid. The glucocorticoid receptor can be distinguished from other glucocorticoid-binding proteins, based on their steroid specificity and physicochemical properties. There is no clear-cut demonstration that the receptor differs from tissue to tissue, and it is in fact very similar in various species. Unlike in other systems, receptor concentration does not seem to be regulated by its ligand or by other hormones. However, certain cases of hypo- as well as hypersensitivity to glucocorticoids appear to result from changes at the receptor level. The data indicate that the receptor can exist in inactive and active forms. The former predominate in the absence of steroid or when an angatonist is bound. Glucocorticoid agonists bind the active form, allowing it to be "activated" and subsequently bound to the nucleus. All of the receptors in isolated cytosol do not appear to be available for immediate occupancy by an agonist and this may be due to the time required for conversion of the receptors from inactive to active forms. The correlations between receptor binding and the glucocorticoid response indicate that the receptor is a rate-limiting factor in the magnitude and kinetics of the response, and this finding has important implications regarding mechanisms.

Animals↗
PubMed1993

Fibroblast growth factor receptor-1, interleukin-1 receptor, and glucocorticoid receptor messenger RNA production in the human lacrimal gland.

PURPOSE: To determine whether messenger RNA coding for fibroblast growth factor receptor-1, interleukin-1 receptor, and glucocorticoid receptor messenger RNA are produced in human lacrimal tissue. METHODS: Total cellular RNA was isolated from three specimens of normal human lacrimal tissue and complementary DNA was synthesized. The polymerase chain reaction and sequence-specific primers were used to amplify the sequences of interest from the complementary DNA. Hot blotting and sequence-specific probes were used to demonstrate that the expected amplification products were specific. RESULTS: Data demonstrated that fibroblast growth factor receptor-1, interleukin-1 receptor, and glucocorticoid receptor messenger RNA are produced in human lacrimal tissue. CONCLUSIONS: These results and the previous identification of basic fibroblast growth factor in the lacrimal gland suggest that basic fibroblast growth factor has autocrine or paracrine functions in lacrimal tissue. More study is needed to determine whether the corresponding proteins are produced and, if so, what functions are regulated by fibroblast growth factor receptor-1, interleukin-1 receptor, and glucocorticoid receptor in the lacrimal gland.

Base Sequence↗
PubMed2003

The pursuit of differentiated ligands for the glucocorticoid receptor.

Glucocorticoids have a pervasive role in human health and physiology. The endogenous members of this family are involved in a breadth of endocrine functions including metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance, as well as maintenance of immunological, renal and skeletal homeostasis. The predominant mode of action of glucocorticoids involves regulation of gene expression via the glucocorticoid receptor (GR). Synthetic glucocorticoids have long been the standard for the treatment of inflammatory and immune disorders, yet the benefits of classic steroids such as dexamethasone and prednisolone are accompanied by well-characterized potentiation of homeostatic endocrine functions, leading to the side effects associated with prolonged treatment. In recent campaigns for safer analogs, compounds have been sought which differentiate functional repression of existing transcription factors such as AP-1 and NFkappaB from GR-mediated transcriptional activation arising from binding at glucocorticoid-receptor response elements (GREs). Such differentiated ligands would provide the desired immunoregulatory actions without the endogenous changes in gene expression associated with undifferentiated steroids. We detail the methods for the evaluation of selective GR modulators and describe the evolution of new compounds where varying degrees of selectivity have been reported.

Animals↗
PubMed2004

Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor.

Glucocorticoids (Gc) act through the glucocorticoid receptor (GR) to enhance or repress transcription of glucocorticoid-responsive genes depending on the promoter and cellular context. Repression of proopiomelanocortin (POMC) gene expression by Gc was proposed to use different mechanisms. We described the POMC promoter Nur response element (NurRE) as a target for Gc repression. NGFI-B (Nur77), an orphan nuclear receptor, and two related factors, Nurr1 and NOR1, bind the NurRE as homo- or heterodimers to enhance POMC gene expression in response to CRH. Gc antagonize CRH-stimulated as well as NGFI-B-dependent transcription. We now show that GR antagonizes NurRE-dependent transcription induced by all members of the Nur77 subfamily and that these nuclear receptors can all interact directly with GR. Transcriptional antagonism as well as direct protein-protein interaction between NGFI-B and GR take place primarily via their respective DNA binding domains, although DNA binding itself and the GR homodimerization interface are not involved. In vivo, GR and Nur factors can be coimmunoprecipitated whereas GR is recruited to the POMC promoter upon glucocorticoid action. Thus, our data suggest a mechanism for transrepression between two nuclear receptors, GR and NGFI-B, that is unique, although quite similar to that proposed for transrepression between GR and activator protein 1 (AP-1) or nuclear factor-kappaB (NFkappaB).

Amino Acid Sequence↗
PubMed2001

Conditioned activity to amphetamine in transgenic mice expressing an antisense RNA against the glucocorticoid receptor.

Glucocorticoids enhance the locomotion-stimulating and the rewarding properties of stimulant drugs. Amphetamine-induced conditioned activity was investigated in B6C3F1 (controls) and antisense transgenic mice. The latter expresses a neurofilament-promotor-driven antisense RNA complementary to a fragment of cDNA that codes for the mouse glucocorticoid receptor. This gene expression leads to approximately a 50% reduction in glucocorticoid receptor mRNA in the brain. Transgenic mice showed an increased novelty response when tested in an open field, in terms of both distance traveled and number of rearings. Moreover, they displayed enhanced amphetamine-induced conditioned activity. Behavioral sensitization was observed in controls, whereas behavioral tolerance developed in transgenic mice. These data support the concept of an enhanced stress response in these transgenic mice, rather than a general downregulation of the stress response because of impaired glucocorticoid receptor function.

Amphetamine↗
PubMed1984

Characterization of the AtT-20 cell's 'repleting' glucocorticoid receptor.

Glucocorticoids deplete the AtT-20 mouse pituitary tumor cell of its glucocorticoid receptors. Once placed into steroid-free medium, however, these 'receptor-deplete' cells gradually regain their ability to bind glucocorticoids displaceably. The goal of this paper is to determine whether replete binding-species is indeed a glucocorticoid receptor, and whether any precursor or modified forms are seen during repletion. Once depleted, cells take nearly 3-4 days to replete their full complement of cytosolic glucocorticoid-binding species. Scatchard analysis revealed only one binding site, of which the affinity for dexamethasone was identical to that of the native receptor. The steroid-binding specificity of the 'replete' binding species was exactly the same as that of the original receptor. The molecular size and surface charge density of the glucocorticoid-binding species obtained throughout the process of repletion were identical to those of the original receptor. Finally, studies in which replete cells were exposed to glucocorticoid agonists showed that the cell was able to decrease its production of ACTH, indicating that the regenerated binding species was able to function as a biologically active glucocorticoid receptor. We conclude that the replete species is a glucocorticoid receptor identical to the original, and that probably no precursor or modified forms of the repleting receptor exist.

Adrenocorticotropic Hormone↗
PubMed2000

The molecular chaperones Hsp90 and Hsc70 are both necessary and sufficient to activate hormone binding by glucocorticoid receptor.

Glucocorticoid receptors must be complexed with Hsp90 in order to bind steroids, and it has been reported that at least three other proteins, Hop, Hsc70, and a J-domain protein (either Hsp40 or Ydj1), are required for formation of active Hsp90-steroid receptor complex. In the present study, we reinvestigated activation of stripped steroid receptors isolated from either L cells or WCL2 cells. Surprisingly, we found, using highly purified proteins, that only Hsp90 and Hsc70 are required for the activation of glucocorticoid receptors in the presence of steroids; in the absence of steroids, either p23 or molybdate are also required as reported previously. Addition of Hop or Ydj1 had no affect on the rate or magnitude of the activation of the stripped receptors, and quantitative Western blots confirmed that neither Hop or Hsp40 were present in our protein preparations or in the stripped receptors. Furthermore, a truncated recombinant Hsp70 that does not bind Hop or Hsp40 was as effective as wild-type Hsp70 in activating stripped receptor. Since Hsc70 does not bind directly to Hsp90 but both proteins bind to Hop, it has been suggested that Hop acts as a bridge between Hsp90 and Hsp70. However, we found that after Hsc70 or Hsp90 bind directly to the stripped receptors, they are fully reactivated by Hsp90 or Hsc70, respectively. We, therefore, conclude that Hsp90 and Hsc70 bind independently to stripped glucocorticoid receptors and alone are sufficient to activate them to bind steroids.

Animals↗
PubMed2006

Pregnancy effects on distribution of progesterone receptors, oestrogen receptor alpha, glucocorticoid receptors, Ki-67 antigen and apoptosis in the bovine interplacentomal uterine wall and foetal membranes.

Until recently, studies dealing with the uterus of the pregnant cow focus primarily on the placentome or on early and late pregnancy. Thus, there is a paucity of information about many aspects of the interplacentomal uterine wall including adherent foetal membranes. Corresponding tissue specimens were collected at the slaughterhouse and in animals undergoing premature caesarean section. Two specimens per month of pregnancy were assessed immunohistochemically for progesterone receptors, oestrogen receptor alpha and glucocorticoid receptors, Ki-67 protein and TUNEL procedure was performed. The latter two methods were employed in three animals each per months 1 and 2, 3 and 4, 7 and 8 and in six animals undergoing caesarean section at days 274 and 275 post insemination or during spontaneous labour. Results indicate that proliferation and apoptosis are of minor importance for tissue homeostasis since both can histochemically be detected only sporadically. Thus, at the sites investigated here, cellular hypertrophy plays an important role for tissue growth during pregnancy. Progesterone receptors, oestrogen receptor alpha and glucocorticoid receptors, however, exhibit cell type and pregnancy stage specific distribution patterns within the tissues assessed. Progesterone receptor immunoreactive scores remained fairly unchanged during pregnancy. Oestrogen receptor alpha scores, however, generally decreased and glucocorticoid receptors increased with ongoing gestation. Progesterone receptors and oestrogen receptor alpha were present in endometrial stroma and in myometrial smooth muscle cells during whole pregnancy. Oestrogen receptor alpha was detectable during whole pregnancy also in uterine glands. Progesterone receptors were, however, present at a very low level at the latter site only during months 1-3 and 6-9. Oestrogen receptor alpha and glucocorticoid receptors may also mediate uterine blood flow since they were present in the tunica media of uterine blood vessels. Results of the present study indicate, that progesterone and its receptor play an important role during whole gestation, mainly for uterine quiescence. Glucocorticoids and their receptors - possibly in cooperation with oestrogens and decreasing amounts of the oestrogen receptor alpha - should trigger processes initiating parturition, such as endometrial prostaglandin production. Further studies - including the periparturient period - should help to understand the exact role of the extraplacental compartment of the uterine wall for the initiation and progress of parturition.

Animals↗
PubMed1999

Dexamethasone enhances serum deprivation-induced necrotic death of rat C6 glioma cells through activation of glucocorticoid receptors.

Glucocorticoids have been shown to be neurotoxic and appear to play a role in neuronal cell loss during aging and following neuropathological insults. However, very little is known about the effects of these steroid hormones on glial cells. The effect of the synthetic glucocorticoid dexamethasone (DEX) on glial cell viability was therefore examined by measuring neutral red uptake into rat C6 glioma cells. Serum deprivation markedly reduced cell viability, and this effect was significantly enhanced by DEX. Electrophoretic analysis showed that the cell damage induced by either serum deprivation alone or in combination with DEX was not accompanied by the degradation of DNA into nucleosomic fragments. Electron microscopic studies confirmed that serum deprivation and glucocorticoid treatment caused necrotic cell death. Furthermore, the effect of DEX on cell viability could be mimicked by the glucocorticoid receptor agonist RU28362, and completely prevented by the glucocorticoid receptor antagonist RU38486. These results indicate that dexamethasone can enhance the necrotic death of glioma cells induced by serum deprivation, suggesting that glucocorticoids may be involved in the chronic alteration of brain function arising from neuropathological damage to glial cells.

Androstanols↗
PubMed1984

Heparin-mediated inactivation and transformation of mammary cytoplasmic glucocorticoid receptor.

Glucocorticoid receptor of lactating mouse mammary gland cytosol was exposed to heparin when the receptor was either steroid-free or steroid-bound. Heparin caused a dose-dependent and time-dependent loss of steroid binding activity (inactivation) of the steroid-free receptor; this heparin-induced inactivation was inhibited by molybdate. In contrast, steroid-bound receptor maintained its steroid binding capacity in the presence of heparin but the heparin caused transformation of receptor as detected by increased binding to DNA-cellulose and ATP-Sepharose. Heparin also converted steroid-bound receptor from the 7-8S form to the 4S form. Molybdate inhibited both the heparin-induced transformation and associated conversion to the 4S form.

Animals↗
PubMed2002

Serotonin regulates hippocampal glucocorticoid receptor expression via a 5-HT7 receptor.

Glucocorticoid receptor expression in primary hippocampal cell cultures was significantly increased with either 10 mM 8-bromo cAMP, 50 nM 5-carboxamidotryptamine (5-CT), a potent 5-HT7 receptor agonist, or 100 nM 5-HT. The effect of 5-HT or 5-CT was blocked with methiothepin or by a protein kinase A inhibitor, but not pindolol. These results suggest that the effects of 5-HT on hippocampal GR expression is mediated by a 5-HT7 receptor.

8-Bromo Cyclic Adenosine Monophosphate↗