Role of the RNA-Binding Protein Tristetraprolin in Glucocorticoid-Mediated Gene Regulation

Ishmael, Faoud T.; Fang, Xi; Galdiero, Maria Rosaria; Atasoy, Ulus; Rigby, William F.C.; Gorospe, Myriam; Cheadle, Chris; Stellato, Cristiana

doi:10.4049/jimmunol.180.12.8342

Cited by 81 publications

(78 citation statements)

References 67 publications

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“…TTP is an important regulator of the decay of a subset of ARE-containing mRNAs (17,21,34,48,56,58). However, since multiple cellular AUBPs other than TTP can recognize the ARE sequence and exert synergistic or opposing effects (40,68), it can be difficult to discern the exact role of TTP in the context of the ARE in cells.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment

Clement

Scheckel

Stoecklin

et al. 2011

Molecular and Cellular Biology

174

192

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mRNA turnover is a critical step in the control of gene expression. In mammalian cells, a subset of mRNAs regulated at the level of mRNA turnover contain destabilizing AU-rich elements (AREs) in their 3 untranslated regions. These transcripts are bound by a suite of ARE-binding proteins (AUBPs) that receive information from cell signaling events to modulate rates of ARE mRNA decay. Here we show that a key destabilizing AUBP, tristetraprolin (TTP), is repressed by the p38 mitogen-activated protein kinase (MAPK)-activated kinase MK2 due to the inability of phospho-TTP to recruit deadenylases to target mRNAs. TTP is tightly associated with cytoplasmic deadenylases and promotes rapid deadenylation of target mRNAs both in vitro and in cells. TTP can direct the deadenylation of substrate mRNAs when tethered to a heterologous mRNA, yet its ability to do so is inhibited upon phosphorylation by MK2. Phospho-TTP is not impaired in mRNA binding but does fail to recruit the major cytoplasmic deadenylases. These observations suggest that phosphorylation of TTP by MK2 primarily affects mRNA decay downstream of RNA binding by preventing recruitment of the deadenylation machinery. Thus, TTP may remain poised to rapidly reactivate deadenylation of bound transcripts to downregulate gene expression once the p38 MAPK pathway is deactivated.

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Section: Resultsmentioning

confidence: 99%

Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment

Clement

Scheckel

Stoecklin

et al. 2011

Molecular and Cellular Biology

174

192

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“…To determine if these pharmacological interventions up-regulated the expression of real genes, we took advantage of data derived from two prior microarray analyses in which glucocorticoid-and cAMP-inducible genes were identified in pulmonary type II A549 cells and BEAS-2B cells, respectively. Several of these genes, including GILZ, p57 kip2 , CD200, CRISPLD2, RGS2, SOCS3, TTP, and BRF-1, could have therapeutic potential in COPD through their ability to suppress proinflammatory mediator release (which may reduce exacerbation frequency), protect against bronchoconstriction, and limit airway remodeling (Samuelsson et al, 1999;Chang et al, 2003;Eddleston et al, 2007;Yoshimura et al, 2007;Ishmael et al, 2008;Snelgrove et al, 2008;Ayroldi and Riccardi, 2009;Wang et al, 2009;Holden et al, 2011). Accordingly, these genes were selected to provide proof of concept.…”

Section: Resultsmentioning

confidence: 99%

Concurrent Agonism of Adenosine A_2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

Greer

Page

Joshi

et al. 2013

J Pharmacol Exp Ther

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Chronic obstructive pulmonary disease (COPD) is a neutrophilic inflammatory disorder that is weakly responsive to glucocorticoids. Identification of ways to enhance the anti-inflammatory activity of glucocorticoids is, therefore, a major research objective. Adenosine receptor agonists that target the A 2B -receptor subtype are efficacious in several cell-based assays and preclinical models of inflammation. Accordingly, the present study was designed to determine if a selective A 2B -receptor agonist, 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulphanyl]acetamide (Bay 60-6583), and a glucocorticoid, dexamethasone, in combination display putative anti-inflammatory activity that is superior to either drug alone. In BEAS-2B human airway epithelial cells stably transfected with cAMP-response element (CRE) and glucocorticoid response element (GRE) reporter constructs, Bay 60-6583 promoted CRE-dependent transcription and enhanced GRE-dependent transcription by an adenosine A 2B -receptor-mediated mechanism that was associated with cAMP formation and abolished by an inhibitor of cAMP-dependent protein kinase. Analysis of the concentration-response relationship that described the enhancement of GRE-dependent transcription showed that Bay 60-6583 increased the magnitude of response without affecting the potency of dexamethasone. Bay 60-6583 and dexamethasone also induced a panel of genes that, collectively, could have benefit in COPD. These were categorized into genes that were induced in a positive cooperative manner (RGS2, p57 kip2 ), an additive manner (TTP, BRL-1), or by Bay 60-6583 (CD200, CRISPLD2, SOCS3) or dexamethasone (GILZ) only. Thus, the gene induction "fingerprints" produced by Bay 60-6583 and dexamethasone, alone and in combination, were distinct. Collectively, through their actions on gene expression, an adenosine A 2B -receptor agonist and a glucocorticoid administered together may have utility in the treatment of inflammatory disorders that respond suboptimally to glucocorticoids as a monotherapy.

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“…This issue is not addressed by the Smoak and Cidlowski (2006) study, so the relative contribution of TTP to feedback control versus glucocorticoiddependent inhibition of TNF-␣ remains open. Likewise, the study of Ishmael et al (2008) used TTP knockout fibroblasts to show a major role for TTP in the glucocorticoid-dependent down-regulation of inflammatory genes. However, complete knockout of TTP induces an inflammatory phenotype by increasing TNF-␣ expression and mRNA stabilization and presumably production of other inflammatory genes (Carballo et al, 1998(Carballo et al, , 2000Lai et al, 2006).…”

Section: Regulation Of Ttp Expression Inmentioning

confidence: 99%

“…The importance of TTP as a negative regulator of inflammatory gene expression is illustrated by the fact that mice in which the TTP gene is lacking demonstrate severe and chronic inflammation via an effect that involves increased TNF-␣ expression (Taylor et al, 1996). In addition to this role in feedback control, TTP expression is also reported to be up-regulated by glucocorticoids, and this may contribute to the post-transcriptional repression of inflammatory gene expression (Smoak and Cidlowski, 2006;Ishmael et al, 2008;Kaur et al, 2008). However, this point remains unclear because TTP expression induced by an inflammatory stimulus is reduced by dexamethasone (Jalonen et al, 2005).…”

mentioning

confidence: 99%

Regulation of Tristetraprolin Expression by Interleukin-1β and Dexamethasone in Human Pulmonary Epithelial Cells: Roles for Nuclear Factor-κB and p38 Mitogen-Activated Protein Kinase

King

Kaur²,

Gong

et al. 2009

J Pharmacol Exp Ther

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The mRNA-destabilizing protein tristetraprolin (TTP) negatively regulates adenine-and uridine-rich element (ARE)-containing mRNAs. In A549 pulmonary cells, TTP mRNA and both a ϳ40-and a ϳ45-kDa phosphorylated version of TTP protein were rapidly induced in response to interleukin (IL)-1␤. Analysis with IB␣⌬N, a dominant version of inhibitor of B␣ (IB␣), as well as dominant-negative and small-molecule IB kinase (IKK) inhibitors demonstrated that IL-1␤-induced TTP is nuclear factor-B (NF-B)-dependent. Likewise, TTP expression and formation of the ϳ45-kDa phosphorylated form of TTP are blocked by the p38 mitogen-activated protein kinase (MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). By contrast, and despite a 3-to 4-fold induction of TTP mRNA, the anti-inflammatory glucocorticoid dexamethasone only modestly induced expression of the ϳ40-kDa form of TTP. In the context of IL-1␤, dexamethasone exerted a marginal repressive effect on TTP mRNA expression and more considerably reduced TTP protein. Given a requirement for p38 MAPK in the induction of TTP by IL-1␤, this repressive effect may be explained by repression of the p38 MAPK pathway by dexamethasone. Knockdown of TTP protein by siRNA elevated IL-1␤-induced expression of granulocyte macrophage-colony-stimulating factor (GM-CSF) and IL-8, demonstrating a role for TTP in feedback control. Likewise, knockdown of TTP increased GM-CSF expression in the presence of IL-1␤ plus dexamethasone, suggesting that feedback control by TTP also occurs in the context of IL-1␤ plus dexamethasone. Taken together, our data demonstrate that NF-B and p38 MAPK are critical to the induction of TTP by IL-1␤ and that TTP induction provides feedback control of the ARE-containing genes GM-CSF and IL-8.Recruitment of inflammatory cells, including neutrophils, monocyte/macrophage, eosinophils, and T cells, is central to inflammation and is driven by increases in the expression of cytokines, chemokines, adhesion molecules, and other inflammatory proteins. For example, activation of structural cells in the airways by inflammatory insult or cytokines, such as interleukin (IL)-1␤ or TNF-␣, leads to the expression and production of IL-8 (CXCL8) and granulocyte macrophagecolony-stimulating factor (GM-CSF) (Laberge and El Bassam, 2004). Because IL-8 is primarily a neutrophil chemoattractant (Mukaida, 2003), whereas GM-CSF stimulates myeloid-derived cells, including basophils, eosinophils, neutrophils, monocyte/ macrophages, as well as subsets of dendritic cells, these two proteins differentially contribute to inflammatory cell influx (Martinez-Moczygemba and Huston, 2003). ABBREVIATIONS: IL, interleukin; TNF, tumor necrosis factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; NF-B, nuclear factor-B; ARE, adenine-and uridine-rich element; MAPK, mitogen-activated protein kinase; TTP, tristetraprolin; ERK, extracellular signalregulated kinase; DMEM, Dulbecco's modified Eagle's medium; PD098059, 2Ј-amino-3Ј-methoxyflavone; U0126, 1...

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Role of the RNA-Binding Protein Tristetraprolin in Glucocorticoid-Mediated Gene Regulation

Cited by 81 publications

References 67 publications

Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment

Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment

Concurrent Agonism of Adenosine A_2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

Regulation of Tristetraprolin Expression by Interleukin-1β and Dexamethasone in Human Pulmonary Epithelial Cells: Roles for Nuclear Factor-κB and p38 Mitogen-Activated Protein Kinase

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Role of the RNA-Binding Protein Tristetraprolin in Glucocorticoid-Mediated Gene Regulation

Cited by 81 publications

References 67 publications

Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment

Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment

Concurrent Agonism of Adenosine A2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

Regulation of Tristetraprolin Expression by Interleukin-1β and Dexamethasone in Human Pulmonary Epithelial Cells: Roles for Nuclear Factor-κB and p38 Mitogen-Activated Protein Kinase

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Concurrent Agonism of Adenosine A_2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease