Human glucocorticoid receptor gene promotor—homologous down regulation

Govindan, Manjapra V.; Pothier, F.; Leclerc, S.; Rathanaswami, Palaniswami; Xie, Boxun

doi:10.1016/0960-0760(91)90197-d

Cited by 35 publications

(29 citation statements)

References 16 publications

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“…In this report we demonstrated conclusively that the transcriptional activator Sp1 associates with a CA box in the 5Ј-flanking region of the rat ␤4 subunit gene and can activate ␤4 promoter/luciferase constructs in transient transfection experiments. The CA box has been demonstrated to bind distinct proteins in a variety of cell types and participates in the regulation of such genes as the T-cell receptor (44), the erythropoietin receptor (45), members of the globin gene family (47)(48)(49), the glucocorticoid receptor (46), and others (52)(53)(54). Indeed, a mutation within the CA box of the ␥-globin gene promoter has been shown to result in the development of ␤-thalassemia (56 -57).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Neuronal Nicotinic Acetylcholine Receptor Genes

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Casanova

Gardner

1996

Journal of Biological Chemistry

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To date, 11 members (␣2-␣9 and ␤2-␤4) of the neuronal nicotinic acetylcholine receptor gene family have been identified. These genes encode subunits that form distinct receptors with different pharmacological and physiological profiles in temporally and spatially restricted patterns within the nervous system. Distinct molecular mechanisms probably orchestrate the expression of various receptor subtypes, yet little is known of specific transcriptional regulatory elements and their associated factors that are responsible for this segregated pattern of expression. Here we report the identification of an element, in the 5-flanking region of the rat ␤4 subunit gene, containing a CA box that is necessary for ␤4 promoter activity in a transiently transfected cholinergic cell line, SN17. This element was shown to interact with a protein(s) in SN17 nuclear extracts that is antigenically related to the transcriptional activator Sp1. Furthermore, co-transfection experiments confirmed that Sp1 can transactivate a ␤4 promoter-reporter gene construct, indicating that Sp1 is necessary, at least in part, for transcriptional activation of the ␤4 subunit gene. Neuronal nicotinic acetylcholine (nACh)1 receptors belong to a large family of related neurotransmitter receptors that are expressed within the central and peripheral nervous systems (CNS and PNS). Little is known of their function within the CNS, although a recent report suggests that presynaptic nACh receptors may modify fast excitatory transmission in the CNS (1). Additionally, the loss of cholinergic neurons in pathological states involving alterations in cognition and memory (e.g. Alzheimer's disease) implicates nACh receptors in these processes (2). In support of this premise, transgenic mice lacking the nACh receptor ␤2 subunit performed poorly in passive avoidance testing, suggesting a defect in associative memory (3). Further underscoring the importance of nACh receptors within the CNS is a recent report describing the development of autosomal dominant, nocturnal, frontal lobe epilepsy in humans, resulting from a missense mutation in the ␣4 subunit gene (4). It is clear that a significant amount of work remains to be done in order to fully understand the function of nACh receptors, including the identification and characterization of individual subunit genes.Eleven members of the nACh receptor gene family have been identified to date, and they include ␣2-␣9 and ␤2-␤4 (5-20). These subunits have been demonstrated in either Xenopus oocytes or in vivo to form a variety of distinct heteromeric (␣2, ␣3, and ␣4 with either ␤2 or ␤4) and homomeric (␣7, ␣8, and ␣9) receptors with different pharmacological and physiological profiles (21-23). This functional heterogeneity likely results from incorporation of different ␣ and ␤ subunits into mature receptors (19,24). Further complicating the characterization of nACh receptors is the observation that individual nACh receptor subunit gene expression occurs in distinct yet overlapping temporally and spatially restricted patterns ...

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Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Neuronal Nicotinic Acetylcholine Receptor Genes

Bigger

Casanova

Gardner

1996

Journal of Biological Chemistry

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“…It is commonly accepted that GR mediates the down-regulation of its own gene by involving a transcriptional mechanism (38)(39)(40). For instance, Burnstein and colleagues (38) showed that an intragenic sequence within the coding sequence of the GR gene is responsible for GC-induced GR homologous down-regulation.…”

Section: Site-specific Phosphorylation Of Gr In Response To Gcs In Asmcsmentioning

confidence: 99%

Cytokines Alter Glucocorticoid Receptor Phosphorylation in Airway Cells

Bouazza

Krytska²,

Debba-Pavard³

et al. 2012

Am J Respir Cell Mol Biol

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Corticosteroid insensitivity (CSI) represents a profound challenge in managing patients with asthma. We recently demonstrated that short exposure of airway smooth muscle cells (ASMCs) to proasthmatic cytokines drastically reduced their responsiveness to glucocorticoids (GCs), an effect that was partially mediated via interferon regulatory factor-1, suggesting the involvement of additional mechanisms (Am J Respir Cell Mol Biol 2008;38:463-472). Although GC receptor (GR) can be phosphorylated at multiple serines in the Nterminal region, the major phosphorylation sites critical for GR transcriptional activity are serines 211 (Ser211) and 226 (Ser226). We tested the novel hypothesis that cytokine-induced CSI in ASMCs is due to an impaired GR phosphorylation. Cells were treated with TNF-a (10 ng/ml) and IFN-g (500 UI/ml) for 6 hours and/or fluticasone (100 nm) added 2 hours before. GR was constitutively phosphorylated at Ser226 but not at Ser211 residues. Cytokines dramatically suppressed fluticasone-induced phosphorylation of GR on Ser211 but not on Ser226 residues while increasing the expression of Ser/Thr protein phosphatase (PP)5 but not that of PP1 or PP2A. Transfection studies using a reporter construct containing GC responsive elements showed that the specific small interfering RNAinduced mRNA knockdown of PP5, but not that of PP1 or PP2A, partially prevented the cytokine suppressive effects on GR-meditated transactivation activity. Similarly, cytokines failed to inhibit GC-induced GR-Ser211 phosphorylation when expression of PP5 was suppressed. We propose that the novel mechanism that proasthmatic cytokine-induced CSI in ASMCs is due, in part, to PP5-mediated impairment of GR-Ser211 phosphorylation.Keywords: serine/threonine protein phosphatase; airway smooth muscle; asthma; corticosteroid insensitivity; airway remodeling Although in the majority of patients with asthma symptoms are well controlled by inhaled glucocorticoids (GCs), a subgroup of patients suffering from severe asthma respond poorly to GC therapy (1, 2). This group is responsible for a disproportionate share of health care costs and morbidity associated with the disease; as a result, corticosteroid insensitivity (CSI) in patients with severe asthma represents a significant unmet clinical need (3). Recent studies performed on bronchial biopsies from patients with asthma showed a persistent expression of eotaxin (4), CCL19 (5), ADAM33, and ADAM8 (6, 7) in airway smooth muscle (ASM) bundles despite patients being treated with inhaled or oral GCs. The expression of these GC-insensitive proasthmatic proteins by ASM correlated with the severity of asthma. We and others replicated this finding in vitro using cultured human ASM cells (ASMCs) exposed to a combination of TNF-a and IFN-g (8-10). We showed that the induction of a variety of proasthmatic genes, namely CD38, CXCL10, CX3CL1, and CCL5, by TNF-a and IFN-g was surprisingly insensitive to the inhibition by GC (9, 11). This "corticosteroidinsensitive" state induced by TNF-a and IFN-g was associate...

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“…It is therefore interesting that most cell types, mainly of nonlymphoid origin, appear to survive GC treatment by decreasing transcription of GR mRNA to reduce GR protein levels (9,10), and that sequences in the GR promoter seem to regulate this process (11). This down-regulation is tissue specific, because GR mRNA and protein levels were increased in the GC-sensitive human CEM-7 and mouse S49 T lymphocyte cell lines upon GC treatment (12,13), and increased GR expression was suggested to be essential for subsequent GICD in T lymphoblasts (14).…”

Section: G Lucocorticoids (Gc)mentioning

confidence: 99%

Expression of the Glucocorticoid Receptor from the 1A Promoter Correlates with T Lymphocyte Sensitivity to Glucocorticoid-Induced Cell Death

Purton

Monk

Liddicoat

et al. 2004

The Journal of Immunology

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Glucocorticoid (GC) hormones cause pronounced T cell apoptosis, particularly in immature thymic T cells. This is possibly due to tissue-specific regulation of the glucocorticoid receptor (GR) gene. In mice the GR gene is transcribed from five separate promoters designated: 1A, 1B, 1C, 1D, and 1E. Nearly all cells express GR from promoters 1B–1E, but the activity of the 1A promoter has only been reported in the whole thymus or lymphocyte cell lines. To directly assess the role of GR promoter use in sensitivity to glucocorticoid-induced cell death, we have compared the activity of the GR 1A promoter with GC sensitivity in different mouse lymphocyte populations. We report that GR 1A promoter activity is restricted to thymocyte and peripheral lymphocyte populations and the cortex of the brain. The relative level of expression of the 1A promoter to the 1B–1E promoters within a lymphocyte population was found to directly correlate with susceptibility to GC-induced cell death, with the extremely GC-sensitive CD4+CD8+ thymocytes having the highest levels of GR 1A promoter activity, and the relatively GC-resistant αβTCR+CD24int/low thymocytes and peripheral T cells having the lowest levels. DNA sequencing of the mouse GR 1A promoter revealed a putative glucocorticoid-response element. Furthermore, GR 1A promoter use and GR protein levels were increased by GC treatment in thymocytes, but not in splenocytes. These data suggest that tissue-specific differences in GR promoter use determine T cell sensitivity to glucocorticoid-induced cell death.

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Human glucocorticoid receptor gene promotor—homologous down regulation

Cited by 35 publications

References 16 publications

Transcriptional Regulation of Neuronal Nicotinic Acetylcholine Receptor Genes

Transcriptional Regulation of Neuronal Nicotinic Acetylcholine Receptor Genes

Cytokines Alter Glucocorticoid Receptor Phosphorylation in Airway Cells

Expression of the Glucocorticoid Receptor from the 1A Promoter Correlates with T Lymphocyte Sensitivity to Glucocorticoid-Induced Cell Death

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