Widespread Negative Response Elements Mediate Direct Repression by Agonist- Liganded Glucocorticoid Receptor

Surjit, Milan; Ganti, Krishna Priya; Mukherji, Atish; Ye, Tao; Hua, Guoqiang; Metzger, Daniel; Li, Mei; Chambon, Pierre

doi:10.1016/j.cell.2011.03.027

Cited by 457 publications

(447 citation statements)

References 64 publications

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“…Our search of the β-arrestin-2 gene for GR-binding sites did not reveal a classic GRE; however, it did uncover five sites with high homology to the inverted repeat negative GRE (nGRE), which was recently reported to mediate glucocorticoid-dependent repression of many target genes (17). Two nGREs were located upstream of the transcription start site, and single nGREs were found within intron-1, intron-5, and intron-11.…”

Section: Resultsmentioning

confidence: 97%

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Oakley

Revollo

Cidlowski

2012

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the most common target of therapeutic drugs. The nonvisual arrestins, β-arrestin-1 and β-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, β-arrestins terminate G protein-dependent responses (desensitization) and stimulate β-arrestin-dependent signaling pathways. Alterations in the cellular complement of β-arrestin-1 and β-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control β-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate β-arrestin-1 and β-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of β-arrestin-1 and repress the expression of β-arrestin-2. Glucocorticoid-dependent regulation involves the recruitment of ligand-activated glucocorticoid receptors to conserved and functional glucocorticoid response elements in intron-1 of the β-arrestin-1 gene and intron-11 of the β-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of β-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing β-arrestin-1-dependent stimulation of the MAPK pathway by protease activated receptor 1. These studies demonstrate that glucocorticoids redirect the signaling profile of GPCRs via alterations in β-arrestin gene expression, revealing a paradigm for cross-talk between nuclear and cell surface receptors and a mechanism by which glucocorticoids alter the clinical efficacy of GPCR-based drugs.

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Section: Resultsmentioning

confidence: 97%

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Oakley

Revollo

Cidlowski

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…All 3-keto SRs-comprising of the glucocorticoid, mineralocorticoid, and androgen and progesterone receptors-are capable of binding to (+)GREs. The structural basis of GR-mediated transcriptional repression has remained less clear; however, recent work has shown that negative glucocorticoid response elements, or nGREs, play a role in GR-mediated transcriptional repression (12). At nGREs, monomeric GR DBD binds to an everted repeat with negative cooperativity (14) (Fig.…”

mentioning

confidence: 99%

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Hudson

Kossmann

Vera

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Many genomes contain families of paralogs-proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response elementbinding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.evolution | glucocorticoid | epistasis | steroid receptors

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“…When the GR binds to glucocorticoid, the activated glucocorticoid-GR complex enters into the nucleus and modulates gene transcription. It is becoming widely recognized that in contrast to "simple" GRE [41], which is a transactivation element, no consensus sequence for GREs that confer transcriptional repression has emerged, i.e., this ''tethering'' GRE does not contain DNA binding sites for GR, but instead contains binding sites for other transcription factors that GR can interact with [42]. In this respect, the non-existence of consensus GRE in the human Cbg promoter does not rule out the transrepressive activity of GR, especially because a research using GR-knockout mice revealed that GR is essential for repressing Cbg gene expression in the liver, and for dexamethasone-inhibited CBG expression in the adult liver [39].…”

Section: Discussionmentioning

confidence: 99%

Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

Lei

et al. 2012

Sci. China Life Sci.

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Corticosteroid-binding globulin (CBG) is a high-affinity plasma protein that transports glucocorticoids and progesterone. Others and we have reported non-synonymous single nucleotide polymorphisms (SNPs) that influence CBG production or steroid-binding activity. However, no promoter polymorphisms affecting the transcription of human CBG gene (Cbg) have been reported. In the present study we investigated function implications of six promoter SNPs, including 26 C/G, 54 C/T, 144 G/C, 161 A/G, 205 C/A, and 443/444 AG/, five of which are located within the first 205 base pairs of 5′-flanking region and close to the highly conserved footprinted elements, TATA-box, or CCAAT-box. Luciferase reporter assays demonstrated that basal activity of the promoter carrying 54 T or 161 G was significantly enhanced. The first three polymorphisms, 26 C/G, 54 C/T, and 144 G/C located close to the putative hepatic nuclear factor (HNF) 1 binding elements, altered the transactivation effect of HNF1. We also found a negative promoter response to dexamethasone-activated glucocorticoid receptor (GR) , although none of the SNPs affected its transrepression function. Our results suggest that human Cbg 26 C/G, 54 C/T, 144 G/C, and 161 A/G promoter polymorphisms alter transcriptional activity, and further studies are awaited to explore their association with physiological and pathological conditions. , both of which are well-known hormones for pregnancy maintenance or labor onset. While CBG mainly binds >80% of cortisol in human peripheral blood [3], at the maternal-fetal interface CBG will be occupied by the very high concentrations of progesterone, which is several fold higher than those of cortisol [6]. In the circulation of women during mid-late pregnancy, approximately 10% of CBG steroid-binding sites are occupied by progesterone, versus <1% in non-pregnant women [5]. Plasma CBG levels rise progressively through gestation until term pregnancy [7], and so do blood cortisol and progesterone levels. Maternal plasma CBG, total and free cortisol concentrations are reduced in pre-eclampsia and gestational hypertension patients, and this may be a consequence of decreased Cbg synthesis driven by cytokines or increased degradation driven by inflammation [7]. SPECIAL TOPIC

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Widespread Negative Response Elements Mediate Direct Repression by Agonist- Liganded Glucocorticoid Receptor

Cited by 457 publications

References 64 publications

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

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