The Stability of Tristetraprolin mRNA Is Regulated by Mitogen-activated Protein Kinase p38 and by Tristetraprolin Itself

Tchen, Carmen R.; Brook, Matthew; Saklatvala, Jeremy; Clark, Andrew R.

doi:10.1074/jbc.m402059200

Cited by 140 publications

(156 citation statements)

References 66 publications

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“…ERK1/2 inhibition was also associated with a considerable stabilization of CXCL8 transcript, which, however, could not counteract its suppressive effect on CXCL8 gene transcription, eventually leading to a reduced CXCL8 expression. Most of the studies that analyzed the role of MAPKs on gene transcript turnover have implicated p38 MAPKs or JNKs as relevant contributors to mRNA stability (41,42). Accordingly, we observed that p38␣␤ MAPK inhibition was associated with a reduced stability of both CXCL8 and CCL2 transcripts, hence opposing chemokine expression both at the transcriptional and posttranscriptional level.…”

Section: Discussionmentioning

confidence: 49%

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

Pastore

Mascia

Mariotti

et al. 2005

The Journal of Immunology

168

172

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Resident cell populations of the skin contribute to the inflammatory response by producing an array of chemokines, which attract leukocytes from the circulation. TNF-α is a major inducer of proinflammatory mediators in keratinocytes. We have recently observed that epidermal growth factor receptor (EGFR) signaling affects TNF-α-driven chemokine expression in epidermal keratinocytes, and its functional impairment increases the levels of crucial chemoattractants such as CCL2/MCP-1, CCL5/RANTES, and CXCL10/IFN-γ-inducible protein-10. In this study, we report evidence that EGFR-dependent ERK1/2 activity is implicated in this mechanism. Abrogation of ERK1/2 activity with specific inhibitors increased chemokine expression in keratinocytes by enhancing mRNA stabilization. In mouse models, inflammatory response to irritants and T cell-mediated contact hypersensitivity were both aggravated when elicited in a skin area previously treated with an EGFR or a MAPK kinase 1/2 inhibitor. In contrast, impairment of p38αβ MAPK phosphorylation markedly attenuated these responses. Our data indicate that EGFR-dependent ERK1/2 activity in keratinocytes takes part to a homeostatic mechanism regulating inflammatory responses, and emphasize the distinct role of MAPKs as potential targets for manipulating inflammation in the skin.

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Section: Discussionmentioning

confidence: 49%

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

Pastore

Mascia

Mariotti

et al. 2005

The Journal of Immunology

168

172

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“…Recent studies have shown that the p38 MAPK pathway in particular plays an important role in posttranscriptional regulation that leads to mRNA stabilization (41). The p38 MAPK pathway also strongly induces and activates TTP, which down-regulates TNF␣ (42)(43)(44)(45). Those studies suggested that the p38 MAPK pathway may play a crucial role in regulating the expression of TNF␣ (involving a TTPdependent mechanism); however, the precise mechanism is not completely understood, and less is known about the relationship between TIS11B and the p38 MAPK pathway.…”

Section: Discussionmentioning

confidence: 99%

Butyrate suppresses tumor necrosis factor α production by regulating specific messenger RNA degradation mediated through acis-acting AU-rich element

Fukae¹,

Amasaki²,

Yamashita³

et al. 2005

Arthritis Rheum

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Objective. To study the capacity of butyrate to inhibit production of tumor necrosis factor ␣ (TNF␣) in macrophage-like synoviocytes (MLS) from patients with rheumatoid arthritis (RA), in human peripheral monocytes, and in murine RAW264.7 macrophages.Methods. The concentrations of TNF␣ in culture supernatants of these cells were measured using enzyme-linked immunosorbent assay. The expression levels of various messenger RNAs (mRNA), such as those for TNF␣, the mRNA-binding protein TIS11B, and luciferase, were measured using real-time quantitative polymerase chain reaction. The in vitro effects of butyrate on transcriptional regulation were evaluated by transfection with various reporter plasmids in RAW264.7 macrophages. The effects of TIS11B on TNF␣ expression were examined using an overexpression model of TIS11B in RAW264.7 cells.Results. Butyrate suppressed TNF␣ protein and mRNA production in MLS and monocytes, but paradoxically enhanced transactivation of the TNF␣ promoter. Expression of the AU-rich element (ARE)-binding protein TIS11B was up-regulated by butyrate. Induction of TNF␣ mRNA by lipopolysaccharide was significantly inhibited when TIS11B was overexpressed. Butyrate facilitated the degradation of luciferase transcripts containing the 3-untranslated region (3-UTR) of TNF␣, and this effect was dependent on the ARE in the 3-UTR that is known to be involved in the regulation of mRNA degradation.Conclusion. These results indicate that butyrate suppresses TNF␣ expression by facilitating mRNA degradation mediated through a cis-acting ARE. Butyrate has the ability to regulate TNF␣ at the mRNA level and is therefore a potential therapeutic drug for RA patients.

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“…In addition to the effect of phosphorylation on mRNA ARE binding activity of TTP [3,12,52], phosphorylation may have other functional consequences on the protein, including TTP's stability [33,52,53], autoregulation [32,64], and subcellular localization [51,53]. Phosphorylation of TTP may also affect its association with exosome [65], stress granule [36], nucleoporin CAN/Nup214 [66], and retroviral Tax oncoproteins [67].…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin

Cao¹,

Deterding²,

Blackshear³

2007

Expert Review of Proteomics

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Tristetraprolin (TTP) is a member of the CCCH zinc finger proteins and is an anti-inflammatory protein. Mice deficient in TTP develop a profound inflammatory syndrome with erosive arthritis, autoimmunity and myeloid hyperplasia. TTP binds to mRNA AU-rich elements with high affinity for UUAUUUAUU nucleotides and causes destabilization of those mRNA molecules. TTP is phosphorylated extensively in vivo and is a substrate for multiple protein kinases in vitro. A number of approaches have been used to identify its phosphorylation sites. This article highlights the recent progress and different approaches utilized for the identification of phosphorylation sites in mammalian TTP. Important but limited results are obtained using traditional methods including in vivo labeling, site-directed mutagenesis, phosphopeptide mapping and protein sequencing. Mass spectrometry including MALDI/MS, MALDI/MS/MS, LC/MS/MS, IMAC/MALDI/MS/MS and multidimensional protein identification technology (MudPIT) has led the way in identifying TTP phosphorylation sites. The combination of these approaches has identified multiple phosphorylation sites in mammalian TTP, some of which are predicted by motif scanning to be phosphorylated by several protein kinases. This information should provide the molecular basis for future investigation of TTP's regulatory functions in controlling pro-inflammatory cytokines.

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The Stability of Tristetraprolin mRNA Is Regulated by Mitogen-activated Protein Kinase p38 and by Tristetraprolin Itself

Cited by 140 publications

References 66 publications

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

Butyrate suppresses tumor necrosis factor α production by regulating specific messenger RNA degradation mediated through acis-acting AU-rich element

Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin

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