Mechanism of gene expression by the glucocorticoid receptor: Role of protein‐protein interactions

McEwan, Iain J.; Wright, Anthony P. H.; Gustafsson, Jan‐Åke

doi:10.1002/bies.950190210

Cited by 160 publications

(121 citation statements)

References 71 publications

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“…The activated receptors next translocate to the nucleus and affect gene transcription, either as homodimers binding to hormone response elements in the DNA or as monomers that interfere with other transcription factors, a process that does not require DNA binding of the steroid receptor itself (18,19). When considering potential targets for corticosteroid actions that could result in altered electrical properties of neurones, three obvious classes of target sites can be distinguished ( Fig.…”

Section: Cellular Actions Of Corticosteroid Hormones In Hippocampusmentioning

confidence: 99%

Corticosteroid Actions in the Hippocampus

Joëls

2001

J Neuroendocrinology

180

111

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Corticosteroid hormones can enter the brain and bind to two intracellular receptor types that regulate transcription of responsive genes: (i) the high af®nity mineralocorticoid receptors and (ii) the glucocorticoid receptors with approximately 10-fold lower af®nity. Although most cells in the brain predominantly express glucocorticoid receptors, principal cells in limbic structures such as the hippocampus often contain glucocorticoid as well as mineralocorticoid receptors. Recent electrophysiological studies have examined the consequences of transcriptional regulation via the two receptor types for information transfer in the hippocampus. It was found that, under resting conditions, corticosteroids do not markedly alter electrical activity. However, if neurones are shifted towards more depolarized or hyperpolarized potentials due to the action of neurotransmitters, slow and adaptive effects of the corticosteroid hormones become apparent. In general, mineralocorticoid receptor occupation maintains steady electrical activity in hippocampal neurones. Brief activation of glucocorticoid receptors leads to increased in¯ux of calcium, which normally helps to slowly reverse temporarily raised electrical activity. These slow and persistent corticosteroid actions will alter network function within the hippocampus, thus contributing to behavioural adaptation in response to stress. Modulation of hippocampal activity by corticosteroids also affects hippocampal output (e.g. to inhibitory interneurones which control hypothalamic-pituitary-adrenal axis activity). The enhanced calcium in¯ux after glucocorticoid receptor activation can become a risk factor when cells are simultaneously exposed to strong depolarizing inputs, such as those occuring during ischaemia. Similarly, chronically elevated corticosteroid levels (or lack of corticosteroids) could endanger hippocampal cell function. The latter may contribute to the precipitation of clinical symptoms in diseases associated with chronically aberrant corticosteroid levels.

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Section: Cellular Actions Of Corticosteroid Hormones In Hippocampusmentioning

confidence: 99%

Corticosteroid Actions in the Hippocampus

Joëls

2001

J Neuroendocrinology

180

111

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“…Corticosteroids can affect PG synthesis in several tissues, via a strong blockade at the level of mRNA transcription for COX-2 [8,29] and a weak blockade at the level of mRNA transcription for COX-1 [38], and the inhibition of phospholipase A 2 [2] that synthesizes arachidonic acid from phospholipid [18]. Therefore, corticosteroids, even a low dosage of prednisolone (0.5 mg/kg), are thought to aggravate gastric mucosal adverse effects of reduced dosage ketoprofen (0.25 mg/kg) via the blockade of COX-2 expression and the inhibition of phospholipase A 2 .…”

Section: Disccusionmentioning

confidence: 99%

The Interaction between Orally Administered Non-Steroidal Anti-Inflammatory Drugs and Prednisolone in Healthy Dogs

Narita

Sato

Motoishi

et al. 2007

The Journal of Veterinary Medical Science

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ABSTRACT. The interaction between oral non-steroidal anti-inflammatory drugs (NSAIDs) and prednisolone administered concurrently for 30 days was studied in 18 healthy dogs divided into 3 groups of 6 dogs each: a drug-free negative control group (NC group) given 2 gelatin capsules; a group given meloxicam (0.1 mg/kg) and prednisolone (0.5 mg/kg) (MP group); and a group given a reduced dosage of ketoprofen (0.25 mg/kg, PO) and prednisolone (0.5 mg/kg, PO) (KP group). The dogs were periodically monitored by physical examinations, blood analyses, endoscopic examinations, fecal occult blood tests, renal function tests [effective renal plasma flow (ERPF) and glomerular filtration rate (GFR)], urinalyses [urinary sediments, and urinary micro-albumin to creatinine ratio (UAlb/Cre)], urinary enzyme indices, and haemostatic function tests [buccal mucosa bleeding time (BMBT), cuticle bleeding time (CBT)]. Significant changes were observed in the KP group, including a decrease of ERPF and GFR, an increased UAlb/Cre ratio, prolonged BMBT and CBT, as well as the presence of more severe grades of endoscopic lesions and fecal occult blood. In both the MP and KP groups, abnormal enzymuria with exfoliation of renal tubular epithelial cells in the urine was found. However, no significant changes in any of the other tests were observed in the MP group compared with the NC group. These findings suggest that the combination of NSAIDs, even selective COX-2 inhibitors, with prednisolone may be contraindicated due to the potential for serious adverse effects on the kidneys, the platelets, and the gastrointestinal tract.

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“…The 2 domain (residues 526 -556 in hGR or 544 -573 in rGR) possesses transactivation potential in the context of full-length GR (22), nuclear matrix targeting activity (23), and a binding domain for hsp90 (24). The C-terminal AF2 domain (sometimes called c; residues 727-763 in hGR (25) or 745-781 in rGR, determined also as 752-758 in hGR (26)) forms part of the amphipathic ␣-helix 12 of the ligand binding domain and is responsible for the hormonedependent interaction with coactivators of the p160 family, e.g. SRC-1 (27,28).…”

Section: Glucocorticoids (Gcs)mentioning

confidence: 99%

A Point Mutation of the AF2 Transactivation Domain of the Glucocorticoid Receptor Disrupts Its Interaction with Steroid Receptor Coactivator 1

Kučera

Waltner-Law

Scott³

et al. 2002

Journal of Biological Chemistry

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Glucocorticoids cause a 10-fold increase in hepatic phosphoenolpyruvate carboxykinase (PEPCK) gene transcription through two low affinity glucocorticoid receptor (GR) binding sites and a complex array of accessory factor DNA elements and associated proteins. To analyze how co-activators interact with the GR in this context, we took advantage of the C656G GR mutant that binds ligand with very high affinity. This GR activates PEPCK gene transcription at a 500-fold lower dexamethasone concentration than does wild type GR. Transfected C656G GR containing additional mutations or deletions was tested on PEPCK gene expression in H4IIE hepatoma cells. We found that the AF2 domain is the only one of the three defined transactivation domains in GR that is required for PEPCK gene expression and that mutation of this domain disrupts the direct interaction of GR with steroid receptor coactivator 1 (SRC-1). These data help define the functional interaction between GR and SRC-1 and further define the role of the GR in glucocorticoid-mediated expression of the PEPCK gene. Glucocorticoids (GCs)1 play a central role in carbohydrate metabolism by increasing glucose production, decreasing glucose tolerance, and causing insulin resistance (1). GCs increase glucose production primarily by inducing the transcription of genes that encode gluconeogenic enzymes, including PEPCK, a rate-determining enzyme of gluconeogenesis. GCs increase the rate of transcription of the PEPCK gene by ϳ10-fold (2) through a multicomponent glucocorticoid response unit. The glucocorticoid response unit consists of a tandem array of four accessory factor elements (gAF1-4) 2 that bind HNF4/COUP-TF, HNF3, COUP-TF, and C/EBP␤, respectively, and two nonconsensus glucocorticoid response elements (GR1, GR2) (see Fig. 6, inset) (3, 4). The GR binds to the GR1 and GR2 elements 10 -20 times less avidly than to a consensus GRE (5), and GR1 and GR2 are unable to confer glucocorticoid responsiveness by themselves (6). Mutations that disrupt the binding of GR to GR1 result in a more severe reduction of the GC response than does disruption of binding to GR2 (5).GR belongs to the superfamily of steroid/thyroid/retinoic acid receptor proteins that function as ligand-dependent transcription factors (7). Two transactivation domains (referred to as 1 and 2) were originally identified in the human GR (hGR) (8 -12). An additional region involved in transactivation, AF2, has been mapped (see Fig. 2A, inset) (13-15). The 2 and AF2 domains are both located in the ligand-binding domain (LBD) in the C-terminal regions of GR. The 1 domain (also referred to as enh2 or AF-1; residues 77-262 in hGR or 106 -318 in rat GR (rGR)) is located in the N-terminal region of the GR molecule and is generally considered a major region responsible for transactivation. 1 makes contact with proteins in the basal transcriptional apparatus, including the TATA box-binding protein (TBP), possibly through an intermediary adapter protein(s) (16 -18). The 1 domain is highly acidic and phosphorylated (19,20) an...

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Mechanism of gene expression by the glucocorticoid receptor: Role of protein‐protein interactions

Cited by 160 publications

References 71 publications

Corticosteroid Actions in the Hippocampus

Corticosteroid Actions in the Hippocampus

The Interaction between Orally Administered Non-Steroidal Anti-Inflammatory Drugs and Prednisolone in Healthy Dogs

A Point Mutation of the AF2 Transactivation Domain of the Glucocorticoid Receptor Disrupts Its Interaction with Steroid Receptor Coactivator 1

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