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

The addition of insulin or insulin-like growth factor I (IGF-I) to RIE-1 cells increased the expression of the primary response gene cMG1; dose-response analysis suggested that this effect was mediated largely through type 1 IGF receptors. Insulin/IGF-I did not affect the expression of the cMG1-related genes TIS11 and TIS11d, whereas epidermal growth factor, angiotensin II or 12-O-tetradecanoyl phorbol-13-acetate stimulated the expression of all three genes. Incubation with wortmannin (WM) prevented the insulin/IGF-I-induced elevation of cMG1 mRNA, but not that induced by the other mitogens or the stimulation of mitogen-activated protein kinase by insulin. We conclude that WM-sensitive phosphatidylinositol 3-kinase may be involved in the specific stimulation of cMG1 expression by insulin/IGF-I.
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PMID:Insulin and insulin-like growth factor I stimulate expression of the primary response gene cMG1/TIS11b by a wortmannin-sensitive pathway in RIE-1 cells. 761 73

Tristetraprolin (TTP) is a potential transcription factor that contains three PPPPG repeats and two putative CCCH zinc fingers. TTP is encoded by the early response gene Zfp-36, which is highly expressed in response to growth factors and in several hematopoietic cell lines. In the present studies, we investigated the possibility that TTP is phosphorylated in intact cells. In NIH/3T3 cells that were made to overexpress TTP constitutively, we found that the protein was phosphorylated on serine residues, and that this phosphorylation was rapidly (within 10 min) stimulated by several mitogens. In cell-free assays, recombinant mouse TTP was a substrate for the mitogen-activated protein (MAP) kinase. By a combination of protease digestion experiments and site-directed mutagenesis strategies, we found that serine 220 was phosphorylated by p42 MAP kinase in vitro. Expression of mutant TTP in fibroblasts confirmed that serine 220 was one of the major, mitogen-stimulated phosphorylation sites on the protein in intact cells. These results suggest that TTP may be phosphorylated by MAP kinases in vivo and that this phosphorylation may regulate its function.
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PMID:Phosphorylation of tristetraprolin, a potential zinc finger transcription factor, by mitogen stimulation in intact cells and by mitogen-activated protein kinase in vitro. 776 35

Tristetraprolin (TTP) is the prototype of a group of potential transcription factors that contain two or more unusual CCCH zinc fingers. TTP is encoded by the immediate-early response gene Zfp-36, which is rapidly induced in fibroblasts in response to insulin and other growth factors. Indirect evidence suggests that TTP might function as an inhibitory transcription factor. The present studies evaluated the effect of mitogens on the subcellular localization of TTP using Western blotting of cellular nuclear and cytosolic fractions. In NIH/3T3 mouse fibroblasts that constitutively express TTP, 70% of the protein was located in the nucleus of quiescent, serum-deprived cells. Immunoreactive TTP began to increase in the cytosolic compartment within 1 min of serum stimulation of the cells; this increase in cytosolic protein was essentially complete within 5 min of serum stimulation (81% of total) and was accompanied by a commensurate decrease in nuclear TTP. This translocation was complete well before the increase in TTP synthesis that occurred after serum stimulation. Similar experiments in cells expressing a mutant TTP, in which the major mitogen-activated protein kinase site (serine 220) had been mutated to alanine, revealed normal nuclear to cytosolic translocation after serum stimulation, indicating that phosphorylation of this site is not necessary for this translocation to occur. These results suggest that TTP is rapidly modified in response to mitogens so that it is rapidly released from the nucleus to the cytosol, or that proteins retaining TTP in the nucleus are modified to release it into the cytosol. Thus, TTP's proposed function as a transcription factor, possibly an inhibitory one, may be regulated in cells in part by a novel mechanism, i.e. that of rapid, mitogen-stimulated translocation out of the cellular nucleus.
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PMID:Mitogens stimulate the rapid nuclear to cytosolic translocation of tristetraprolin, a potential zinc-finger transcription factor. 882 54

TIS11, a CCCH zinc finger protein, is one of the typical growth factor-inducible nuclear proteins. We found that TIS11 possesses the potential to activate transcription when fused to the GAL4 DNA binding domain and transiently cotransfected into rat pheochromocytoma PC12 cells along with a GAL4-responsive luciferase reporter gene. The study with deletion mutants of TIS11 revealed that the major transactivation region is located at the N-terminal 101 amino acid residues and that the remaining central and C-terminal region had a moderate transactivational activity. In addition, the transactivational activity of TIS11 was found to be significantly reduced by treating the transfectants with phorbol 12-myristate 13-acetate (PMA). PMA-induced inactivation of TIS11 was blocked by calphostin C, a protein kinase C inhibitor, and PD98059, a mitogen-activated protein (MAP) kinase kinase inhibitor. These results suggested that TIS11 functions as a positive transcriptional regulator and that the protein kinase C/MAP kinase signaling cascade is involved in negative regulation of TIS11 by PMA.
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PMID:Transcriptional activation function of zinc finger protein TIS11 and its negative regulation by phorbol ester. 1091 71

To understand the mechanism underlying the transcriptional regulation of the immediate early gene TIS11, we characterized the 5'-flanking region of the rat TIS11 gene. When fused to the luciferase reporter gene, the 5.3-kb 5'-flanking region of the rat TIS11 gene exhibited functional promoter activity in pheochromocytoma PC12 and hepatoma H4IIE cells. 5'-Deletion analyses indicated that multiple negative and positive regulatory regions were present in the 5'-flanking region, and that some of these regions functioned in a cell type-specific manner. Promoter activity of the rat TIS 11 gene was enhanced by phorbol 12-myristate 13-acetate (PMA) in both cell lines, and the PMA-responsiveness resided within the 5'-flanking region. The induction of promoter activity by PMA was completely blocked by GF109203X or PD98059, inhibitors of protein kinase C and mitogen-activated protein (MAP) kinase kinase, respectively. These results suggested that induction of the rat TIS 11 promoter by PMA is mediated by activation of the protein kinase C/MAP kinase cascade.
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PMID:Characterization of the 5'-flanking region of the rat TIS11 gene. 1119 80

Interleukin-10 (IL-10) is a key inhibitory signal of inflammatory responses that regulates the production of potentially pathogenic cytokines like tumor necrosis factor (TNF). We show here that the development of chronic intestinal inflammation in IL-10-deficient mice requires the function of TNF, indicating that the IL-10/TNF axis regulates mucosal immunity. We further show that IL-10 targets the 3' AU-rich elements (ARE) of TNF mRNA to inhibit its translation. Moreover, IL-10 does not alter TNF mRNA stability, and its action does not require the presence of the stability-regulating ARE binding factor tristetraprolin, indicating a differential assembly of stability and translation determinants on the TNF ARE. Inhibition of TNF translation by IL-10 is exerted mainly by inhibition of the activating p38/MAPK-activated protein kinase-2 pathway. These results demonstrate a physiologically significant cross-talk between the IL-10 receptor and the stress-activated protein kinase modules targeting TNF mRNA translation. This cross-talk is necessary for optimal TNF production and for the maintenance of immune homeostasis in the gut.
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PMID:Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. 1144 17

AU-rich elements (ARE) present in the 3' untranslated regions of many cytokines and immediate-early genes are responsible for targeting the transcripts for rapid decay. We present evidence from cotransfection experiments in NIH 3T3 cells that two signaling pathways, one involving phosphatidylinositol 3-kinase (PI3-K), and one involving the p38 mitogen-activated protein kinase (MAPK), lead to stabilization of interleukin-3 mRNA in parallel. Stabilization mediated by either of the two pathways was antagonized by tristetraprolin (TTP), an AU-binding protein known to promote constitutive decay of ARE-containing transcripts. Remarkably, the stabilizing AU-binding protein HuR, in collaboration with p38 MAPK but not with PI3-K, could overcome the destabilizing effect of TTP. These data argue that the stabilizing kinases PI3-K and p38 MAPK do not act through direct inactivation of TTP but via activating pathway-specific stabilizing AU-binding proteins. Our data suggest an integrated model of mRNA turnover control, where stabilizing (HuR) and destabilizing (TTP) AU-binding proteins compete and where the former are under the positive control of independent phosphokinase signaling pathways.
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PMID:Parallel and independent regulation of interleukin-3 mRNA turnover by phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase. 1148 17

Signal transduction pathways regulate gene expression in part by modulating the stability of specific mRNAs. For example, the mitogen-activated protein kinase (MAPK) p38 pathway mediates stabilization of tumor necrosis factor alpha (TNF-alpha) mRNA in myeloid cells stimulated with bacterial lipopolysaccharide (LPS). The zinc finger protein tristetraprolin (TTP) is expressed in response to LPS and regulates the stability of TNF-alpha mRNA. We show that stimulation of RAW264.7 mouse macrophages with LPS induces the binding of TTP to the TNF-alpha 3' untranslated region. The p38 pathway is required for the induction of TNF-alpha RNA-binding activity and for the expression of TTP protein and mRNA. Following stimulation with LPS, TTP is expressed in multiple, differentially phosphorylated forms. We present evidence that phosphorylation of TTP is mediated by the p38-regulated kinase MAPKAPK2 (MAPK-activated protein kinase 2). Our findings demonstrate a direct link between a specific signal transduction pathway and a specific RNA-binding protein, both of which are known to regulate TNF-alpha gene expression at a posttranscriptional level.
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PMID:Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. 1153 35

Oocytes are released from meiotic prophase I arrest through a process termed oocyte maturation. We present here a genetic characterization of oocyte maturation, using C. elegans as a model system. We show that two TIS11 zinc finger-containing proteins, OMA-1 and OMA-2, express specifically in maturing oocytes and function redundantly in oocyte maturation. Oocytes in oma-1;oma-2 mutants initiate but do not complete maturation and arrest at a defined point in prophase I. Two maturation signal-induced molecular events, including the maintenance of activated MAP kinase, do not occur in Oma oocytes. The Oma prophase arrest is released by inactivation of a MYT-1-like kinase, suggesting that OMA-1 and OMA-2 function upstream of MYT-1 as positive regulators of prophase progression during meiotic maturation.
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PMID:Two zinc finger proteins, OMA-1 and OMA-2, are redundantly required for oocyte maturation in C. elegans. 1170 79

The phenotype of mitogen-activated protein kinase-activated protein kinase-2 (MK2) knockout mice revealed the essential role of this enzyme in post-transcriptional regulation of lipopolysaccharide-induced expression of cytokines such as tumour necrosis factor (TNF)-alpha, interleukin-6 and interferon-gamma, at the level of mRNA stability and translation. In the case of TNF-alpha, this regulation depends on the AU-rich element in TNF-alpha mRNA. In addition to cytokine expression, MK2 is also essential for cell migration in vitro. Although the role of MK2 in cytokine expression depends mainly on catalytic activity, its role in cell migration is also dependent on a proline-rich N-terminal motif. However, the molecular mechanisms involved and the relevant protein targets for MK2 are not completely defined. Here we discuss the possible mechanisms by which two potential target proteins of MK2, small heat-shock protein 25/27 (Hsp25/27) and tristetraprolin, could contribute to our understanding of the above regulation.
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PMID:Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression? 1244 Sep 54


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