Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effect of thalidomide on transcriptional and post-transcriptional cyclooxygenase-2 (COX-2) expression, including a pathway leading to COX-2 mRNA destabilization. We found that thalidomide inhibited the interleukin-1beta (IL-1beta)-mediated induction of COX-2 protein and mRNA in Caco-2 cells. Transient transfection with a COX-2 promoter construct demonstrated that thalidomide did not affect IL-1beta-induced transcriptional activation of COX-2, although it did decrease the stability of COX-2 mRNA and suppress IL-1beta-induced cytoplasmic shuttling of an mRNA stabilizing protein, HuR. Thalidomide also suppressed IL-1beta-induced p38 mitogen-activated protein kinase (MAPK) activation, while a p38 MAPK inhibitor destabilized COX-2 mRNA and the cytoplasmic shuttling of HuR induced by IL-1beta. These data suggest that one of the molecular mechanisms of thalidomide may be destabilization of COX-2 mRNA through inhibition of cytoplasmic shuttling of HuR and p38 MAPK.
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PMID:Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR. 1720 22

Toll-like receptor 4 (TLR4) initiates the inflammatory response in blood vessels in reaction to immune stimuli such as lipopolysaccharide (LPS) produced by gram-negative bacteria. LPS-induced proliferation and functional perturbation in vascular smooth muscle cells play important roles during atherogenesis. Ginkgo biloba extract is an antiatherothrombotic Chinese herbal medicine with anti-inflammatory properties. The effects of G. biloba extract on LPS-induced proliferation and TLR4 expression and the underlying mechanisms for these actions, in human aortic smooth muscle cells (HASMCs), were examined in vitro. LPS-induced proliferation was mediated by the expression of TLR4 in HASMCs. LPS increased the expression of TLR4 in HASMCs, and this effect was mediated by the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, phosphorylation of intracellular mitogen-activated protein kinases (MAPKs), and increases in the cytoplasmic level of HuR and TLR4 mRNA stability. G. biloba extract inhibited LPS-induced HASMC proliferation and decreased the expression of TLR4 by inhibiting LPS-induced NADPH oxidase activation, mRNA stabilization, and MAPK signaling pathways. These results suggest that LPS-induced TLR4 expression contributes to HASMC proliferation and that G. biloba inhibits LPS-stimulated proliferation of HASMCs by decreasing TLR4 expression.
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PMID:Ginkgo biloba extract inhibits endotoxin-induced human aortic smooth muscle cell proliferation via suppression of toll-like receptor 4 expression and NADPH oxidase activation. 1726 29

A number of highly regulated gene classes are regulated post-transcriptionally at the level of mRNA stability. A central feature in these mRNAs is the presence of A+U-rich elements (ARE) within their 3' UTRs. Two ARE binding proteins, HuR and AUF1, are associated with mRNA stabilization and destabilization, respectively. Previous studies have demonstrated homomultimerization of each protein and the capacity to bind simultaneous or competitively to a single ARE. To investigate this possibility further, cell biological and biophysical approaches were undertaken. Protein-protein interaction was monitored by fluorescence resonance energy transfer (FRET) and by immunocytochemistry in live and fixed cells using fluorescently labeled CFP/YFP fusion proteins of HuR and p37AUF1. Strong nuclear FRET between HuR/HuR and AUF1/AUF1 homodimers as well as HuR/AUF1 heterodimers was observed. Treatment with the MAP kinase activator, anisomycin, which commonly stabilizes ARE-containing mRNAs, caused rapid nuclear to cytoplasmic shuttling of HuR. AUF1 also underwent shuttling, but on a longer time scale. After shuttling, HuR/HuR, AUF1/AUF1, and HuR/AUF1, FRET was also observed in the cytoplasm. In further studies, arsenite rapidly induced the formation of stress granules containing HuR and TIA-1 but not AUF1. The current studies demonstrate that two mRNA binding proteins, HuR and AUF1, are colocalized and are capable of functional interaction in both the nucleus and cytoplasm. FRET-based detection of AUF1/HuR interaction may serve as a basis of opening up new dimensions in delineating the functional interaction of mRNA binding proteins with RNA turnover.
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PMID:FRET-detectable interactions between the ARE binding proteins, HuR and p37AUF1. 1762 45

The G(0) growth arrest (quiescent) state is highly conserved in evolution to promote survival under adverse environmental conditions. To maintain viability, G(0) growth arrested cells limit gene expression to essential growth control and pro-survival genes. CCAAT enhancer binding protein delta (C/EBPdelta), a member of the C/EBP family of nuclear proteins, is highly expressed in G(0) growth arrested mammary epithelial cells (MECs). Although C/EBPdelta gene transcription is elevated during G(0) growth arrest, C/EBPdelta mRNA and protein are relatively short lived, suggesting tight control of the cellular C/EBPdelta content in unstressed, quiescent cells. Treatment of G(0) growth arrested MECs with ultraviolet radiation (UVR) dramatically increases the C/EBPdelta mRNA half-life (approximately 4-fold) and protein content (approximately 3-fold). The mRNA stabilizing effects of UVR treatment are mediated by the C/EBPdelta mRNA 3'untranslated region, which contains an AU rich element. UVR increased p38 MAP kinase (MAPK) activation and SB203580, a p38 MAPK inhibitor, blocked UVR-induced C/EBPdelta mRNA stabilization. UVR increased the nuclear to cytoplasmic translocation of HuR, an ARE-binding protein that functions in mRNA stabilization. Finally, HuR siRNA treatment blocked UVR-induced stabilization of the C/EBPdelta and C/EBPbeta mRNAs but had no effect on C/EBPzeta (CHOP) mRNA stability. In summary, G(0) growth arrested MECs respond to UVR treatment by activating p38 MAPK, increasing HuR translocation and HuR/C/EBPdelta mRNA binding and stabilizing the C/EBPdelta mRNA. These results identify post-transcriptional stabilization of the C/EBPdelta mRNA as a mechanism to increase C/EBPdelta levels in the stress response of quiescent cells to UVR.
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PMID:Ultraviolet radiation (UVR) activates p38 MAP kinase and induces post-transcriptional stabilization of the C/EBPdelta mRNA in G0 growth arrested mammary epithelial cells. 1790 60

Tristetraprolin (TTP) is a zinc-finger-containing AU-rich elements (ARE)-binding protein. AREs presented in the 3'untranslated region (UTR) of mRNAs from many proto-oncogenes, cytokines, and growth factors may be targets for regulation of messenger RNA stability. In this study, we observed that many immediate early genes (IEGs) were induced during the early differentiation of 3T3-L1 preadipocytes and their ARE-containing transcripts were degraded rapidly. Immunoprecipitation followed by RT-PCR analysis showed that two of IEG mRNAs, COX-2 (cyclooxygenase-2) and MKP-1 (mitogen-activated protein kinase phosphatase), were the target of TTP. Biotinylated MKP-1 AREs also could bring down TTP and the other ARE-binding protein HuR. RNA EMSA and competition assays showed that each of three AREs located in 3'UTR of MKP-1 mRNA has differential binding affinity to TTP. Sequence analysis of 3'UTR of IEG mRNAs suggested that TTP may prefer binding to UUAUUUAUU sequence. Taken together, our results implied that TTP may target specific ARE-containing IEGs' mRNAs such as COX-2 and MKP-1 mRNAs to modulate their expression post-transcriptionally.
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PMID:Modulation of immediate early gene expression by tristetraprolin in the differentiation of 3T3-L1 cells. 1797 Dec 98

Tumor necrosis factor-alpha (TNF-alpha) production is regulated by transcriptional and posttranscriptional mechanisms. Lipopolysaccharide activates the NFkappaB pathway increasing TNF-alpha transcription. Lipopolysaccharide also activates the mitogen-activated protein kinase pathways, resulting in stabilization and enhanced translation of the TNF-alpha message. In addition, nuclear export of the TNF-alpha mRNA is a posttranscriptionally regulated process involving the Tpl2-ERK pathway and requiring the presence of the TNF-alpha AU-rich element (ARE). We demonstrate that nuclear export of the TNF-alpha message requires not only the TNF-alpha ARE but also the interaction of the proteins TAP and NxT1, both of which are involved in nucleocytoplasmic transport of mRNA. Through the use of dominant negative ERK1 and ERK2, we establish that control of TNF-alpha mRNA nuclear export operates specifically through ERK1. Finally, we examined the role of two established TNF-alpha ARE-binding proteins, HuR and tristetraprolin, that shuttle between the nucleus and cytoplasm. These data demonstrate that neither tristetraprolin nor HuR is required for TNF-alpha mRNA export. It is unclear at this time if ARE-binding protein(s) directly interact with the TAP-NxT1 complex, if each complex is independently targeted by ERK1, or if only one complex is targeted.
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PMID:Extracellular signal-regulated kinase regulation of tumor necrosis factor-alpha mRNA nucleocytoplasmic transport requires TAP-NxT1 binding and the AU-rich element. 1804 58

The p75(NTR) acts as a tumor suppressor in the prostate, but its expression is lost as prostate cancer progresses and is minimal in established prostate cancer cell lines such as PC-3, DU-145, and LNCaP. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75(NTR) expression in PC-3 and DU-145 cells leading to p75(NTR)-mediated decreased survival. Here, we investigate the mechanism by which these drugs induce p75(NTR) expression. We show that the observed increase in p75(NTR) protein due to R-flurbiprofen and ibuprofen treatment was accompanied by an increase in p75(NTR) mRNA, and this increase in mRNA was the result of increased mRNA stability and not by an up-regulation of transcription. In addition, we show that treatment with R-flurbiprofen or ibuprofen led to sustained activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Furthermore, inhibition of the p38 MAPK pathway with the p38 MAPK-specific inhibitor SB202190 or by small interfering RNA (siRNA) knockdown of p38 MAPK protein prevented induction of p75(NTR) by R-flurbiprofen and ibuprofen. We also observed that siRNA knockdown of MAPK-activated protein kinase (MK)-2 and MK3, the kinases downstream of p38 MAPK that are responsible for the mRNA stabilizing effects of the p38 MAPK pathway, also prevented an induction of p75(NTR) by R-flurbiprofen and ibuprofen. Finally, we identify the RNA stabilizing protein HuR and the posttranscriptional regulator eukaryotic translation initiation factor 4E as two possible mechanisms by which the p38 MAPK pathway may increase p75(NTR) expression. Collectively, the data suggest that R-flurbiprofen and ibuprofen induce p75(NTR) expression by increased mRNA stability that is mediated through the p38 MAPK pathway.
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PMID:The p38 MAPK pathway mediates aryl propionic acid induced messenger rna stability of p75 NTR in prostate cancer cells. 1805 68

Regulation of mRNA stability by p38 MAPK has been linked to adenosine-uridine-rich elements (AURE) within the 3'-untranslated region (3'UTR) of mRNA. Using microarrays, we previously found that AURE-containing mRNA is over-represented among transcripts up-regulated by NO(*), an activator of p38 MAPK. Here, we investigated NO(*)-induced mRNA stabilization of specific AURE-containing genes to determine the sequence specificity and protein-binding interactions associated with this effect. IL-8, TNF-alpha, and p21/Waf1 3'UTRs were inserted into a luciferase (LUC) reporter gene system and found to decrease LUC activity and mRNA half-life in transfected THP-1 cells. The inhibitory effect of these 3'UTRs on LUC expression inversely correlated with the number of AUUUA motifs. Sequence truncation of the IL-8 3'UTR revealed that two segments, one with AURE sites and another without, contributed to mRNA destabilization. NO(*) activation of p38 MAPK increased LUC activity and mRNA half-life for reporter constructs that contained either of these IL-8 3'UTR segments. AURE-dependent and -independent NO(*) effects were blocked by p38 MAPK inhibition, and AURE-dependent effects were also blocked by site-directed mutagenesis of AUUUA sites. Two proteins, HuR and heterogeneous nuclear ribonucleoprotein A0, were identified, which bound to the AURE-containing region of exogenous and endogenous IL-8 mRNA in a NO(*)-p38 MAPK-dependent manner. These results demonstrate that NO(*)-p38 MAPK signaling can stabilize mRNA via AURE-dependent and -independent mechanisms.
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PMID:Nitric oxide-p38 MAPK signaling stabilizes mRNA through AU-rich element-dependent and -independent mechanisms. 1821 58

Malignant gliomas are highly aggressive tumors of the central nervous system that rely on production of growth factors for tumor progression. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and tumor necrosis factor-alpha, for example, are up-regulated in these tumors to promote angiogenesis and proliferation. RNA stability, mediated through adenine and uridine-rich elements (ARE) in the 3' untranslated region, is a critical control point for regulating these growth factors. RNA half-life is predominantly governed by a balance between stabilizing and destabilizing factors that bind to ARE. We have previously shown that the stabilizing factor HuR is overexpressed in malignant gliomas and linked to RNA stabilization of angiogenic growth factors. Here, we report that the destabilizing factor tristetraprolin (TTP) is also ubiquitously expressed in primary malignant glioma tissues and cell lines. In contrast to benign astrogliotic tissues, however, the protein was hyperphosphorylated, with evidence implicating the p38/mitogen-activated protein kinase (MAPK) pathway. Conditional overexpression of TTP as a transgene in malignant glioma cells led to RNA destabilization of IL-8 and VEGF and down-regulation of protein production. Analysis of in vivo RNA binding indicated a shift of mRNA toward ectopic TTP and away from endogenous HuR. This biochemical phenotype was associated with a decrease in cell proliferation, loss of cell viability, and apoptosis. We postulate that hyperphosphorylation of TTP via p38/MAPK promotes progression of malignant gliomas by negatively regulating its RNA destabilizing function.
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PMID:Tristetraprolin down-regulates interleukin-8 and vascular endothelial growth factor in malignant glioma cells. 1824 66

The mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) plays a major role in dephosphorylating and thereby inactivating the MAP kinases extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. Here, we examine the posttranscriptional events underlying the robust MKP-1 induction by oxidants in HeLa cells. H(2)O(2) treatment potently stabilized the MKP-1 mRNA and increased the association of MKP-1 mRNA with the translation machinery. Four RNA-binding proteins (RNA-BPs) that influence mRNA turnover and/or translation (HuR, NF90, TIAR, and TIA-1) were found to bind to biotinylated transcripts spanning the MKP-1 AU-rich 3' untranslated region. By using ribonucleoprotein immunoprecipitation analysis, we showed that H(2)O(2) treatment increased the association of MKP-1 mRNA with HuR and NF90 and decreased its association with the translational repressors TIAR and TIA-1. HuR or NF90 silencing significantly diminished the H(2)O(2)-stimulated MKP-1 mRNA stability; HuR silencing also markedly decreased MKP-1 translation. In turn, lowering MKP-1 expression in HuR-silenced cultures resulted in substantially elevated phosphorylation of JNK and p38 after H(2)O(2) treatment. Collectively, MKP-1 upregulation by oxidative stress is potently influenced by increased mRNA stability and translation, mediated at least in part by the RNA-BPs HuR and NF90.
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PMID:MKP-1 mRNA stabilization and translational control by RNA-binding proteins HuR and NF90. 1849 Apr 44


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