Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we evaluated the ability of GPI-anchored mucin-like glycoproteins purified from Trypanosoma cruzi trypomastigotes (tGPI-mucin) to trigger phosphorylation of different mitogen-activated protein kinases (MAPKs) and related transcription factors in inflammatory macrophages. Kinetic experiments show that the peak of extracellular signal-related kinase (ERK)-1/ERK-2, stress-activated protein kinase (SAPK) kinase-1/mitogen-activated protein kinase (MAPK) kinase-4, and p38/SAPK-2, phosphorylation occurs between 15 and 30 min after macrophage stimulation with tGPI-mucin or GPI anchors highly purified from tGPI-mucins (tGPI). The use of the specific inhibitors of ERK-1/ERK-2 (PD 98059) and p38/SAPK-2 (SB 203580) phosphorylation also indicates the role of MAPKs, with possible involvement of cAMP response element binding protein, in triggering TNF-alpha and IL-12 synthesis by IFN-gamma-primed-macrophages exposed to tGPI or tGPI-mucin. In addition, tGPI-mucin and tGPI were able to induce phosphorylation of I kappa B, and the use of SN50 peptide, an inhibitor of NF-kappa B translocation, resulted in 70% of TNF-alpha synthesis by macrophages exposed to tGPI-mucin. Finally, the similarity of patterns of MAPK and I kappa B phosphorylation, the concentration of drugs required to inhibit cytokine synthesis, as well as cross-tolerization exhibited by macrophages exposed to tGPI, tGPI-mucin, or bacterial LPS, suggest that receptors with the same functional properties are triggered by these different microbial glycoconjugates.
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PMID:Requirement of mitogen-activated protein kinases and I kappa B phosphorylation for induction of proinflammatory cytokines synthesis by macrophages indicates functional similarity of receptors triggered by glycosylphosphatidylinositol anchors from parasitic protozoa and bacterial lipopolysaccharide. 1120

MUC2 is a secretory mucin normally expressed by goblet cells of the intestinal epithelium. It is overexpressed in mucinous type colorectal cancers but down-regulated in colorectal adenocarcinoma. Phorbol 12-myristate 13-acetate (PMA) treatment of colon cancer cell lines increases MUC2 expression, so we have undertaken a detailed analysis of the effects of PMA on the promoter activity of the 5'-flanking region of the MUC2 gene using stably and transiently transfected promoter reporter vectors. Protein kinase C inhibitors (bisindolylmaleimide, calphostin C) and inhibitors of mitogen-activated protein/extracellular signal regulated kinase kinase (MEK) (PD98059 and U0126) suppressed up-regulation of MUC2. Src tyrosine kinase inhibitor PP2, a protein kinase A inhibitor (KT5720), and a p38 inhibitor (SB 203580) did not affect transcription. Western blotting and reverse transcription-PCR analysis confirmed these results. In addition, co-transfections with mutants of Ras, Raf, and MEK showed that the induction of MUC2 promoter activity by PMA required these three signaling proteins. Our results demonstrate that PMA activates protein kinase C, stimulating MAP kinase through a Ras- and Raf-dependent mechanism. An important role for nuclear factor kappaB (NF-kappaB) was also demonstrated using the inhibitor caffeic acid phenethyl ester and electrophoretic mobility shift assays. Such identification of pathways involved in MUC2 up-regulation by PMA in the HM3 colon cancer cell line may serve as a model for the effects of cytokines and growth factors, which regulate MUC2 expression during the progression of colorectal cancer.
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PMID:Phorbol 12-myristate 13-acetate up-regulates the transcription of MUC2 intestinal mucin via Ras, ERK, and NF-kappa B. 1207 18

Interleukin-1beta (IL-1beta) has been implicated in the pathogenesis of inflammatory diseases of the airway. In this study, we investigated the regulation of MUC2 and MUC5AC expression and of their regulatory mechanisms through cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)). Cells activated by IL-1beta showed increased COX-2, MUC2, and MUC5AC expressions at both the mRNA and protein levels. Mucin production was blocked by the selective COX-2 inhibitor NS398, and PGE(2) directly induced MUC2 and MUC5AC expression at both the mRNA and protein levels in a dose-dependent manner. These results suggest a role for PGE(2) in IL-1beta-induced mucin synthesis in NCI-H292 cells. To investigate the roles of molecules upstream of COX-2 in mucin regulation, we examined the role of mitogen-activated protein kinases (MAPKs). Cells activated by IL-1beta showed increased extracellular signal-regulated kinase (ERK)1/2 and p38 phosphorylation, and IL-1beta-induced MUC2 and MUC5AC production was blocked by the ERK pathway inhibitor PD98059 or the p38 inhibitor SB203580. The inhibition of both MAPKs reduced IL-1beta-induced COX-2 expression and PGE(2) synthesis. Furthermore, the addition of PGE(2) to cells overcame the inhibitory effects of both MAPK inhibitors in IL-1beta-induced mucin production. These results indicate that in human pulmonary epithelial cells, IL-1beta activates ERK or p38 to induce COX-2 production, which in turn induces MUC2 and MUC5AC production.
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PMID:Interleukin-1beta induces MUC2 and MUC5AC synthesis through cyclooxygenase-2 in NCI-H292 cells. 1239 Dec 74

Although tremendous effort has been put towards identifying the surface molecules of nontypeable Haemophilus influenzae (NTHi) for vaccine development over the past decades, it is only recently that we have begun to appreciate the intricate host epithelial signaling networks activated by NTHi, an important human pathogen causing respiratory infections. From what has been reported, it is evident that NTHi activates multiple signaling pathways in host epithelial cells that, in turn, inadvertently contribute to the pathogenesis. Among those signaling pathways, activation of NF-kappaB leads to up-regulation of IL-1beta, IL-8 and TNF-alpha, mucin MUC2 and Toll-like receptor 2 (TLR2), whereas activation of p38 MAP kinase mediates not only up-regulation of inflammatory mediators and mucin MUC5AC but also down-regulation of TLR2. Interestingly, NTHi-induced activation of the PI3K-Akt pathway, however, leads to inhibition of p38 mitogen-activated protein (MAP) kinase. Moreover, the TGF-beta-Smad signaling pathway cooperates with NF-kappaB to mediate up-regulation of mucin MUC2. Finally, glucocorticoids synergistically enhance NTHi-induced TLR2 expression via specific up-regulation of the MAP kinase phosphatase-1 that, in turn, leads to inactivation of p38 MAP kinase, the negative regulator for TLR2 expression. These studies may bring new insights into the molecular pathogenesis of NTHi-induced infections and open up novel therapeutic targets for these diseases.
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PMID:Exploitation of host epithelial signaling networks by respiratory bacterial pathogens. 1268 24

Mucin hypersecretion is commonly observed in many inflammatory diseases of the respiratory tract. MUC5AC is generally recognized to be a major airway mucin because MUC5AC is highly expressed in the goblet cells of human airway epithelium. Moreover, it is regulated by various inflammatory cytokines. However, the mechanisms by which the interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha induce MUC5AC gene expression in normal nasal epithelial cells, and the signal molecules involved, especially in the downstream signaling of mitogen-activated protein (MAP) kinases, remain unclear. Here we show that pharmacologic or genetic inhibition of either ERK or p38 MAP kinase pathway abolished IL-1beta- and TNF-alpha-induced MUC5AC gene expression in normal human nasal epithelial cells. Our results also indicate that the activation of mitogen- and stress-activated protein kinase 1 (MSK1) and cAMP-response element-binding protein and cAMP-response element signaling cascades via ERK and p38 MAP kinases are crucial aspects of the intracellular mechanisms that mediate MUC5AC gene expression. Taken together, these studies give additional insights into the molecular mechanism of IL-1beta- and TNF-alpha-induced MUC5AC gene expression and enhance our understanding on mucin hypersecretion during inflammation.
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PMID:Interleukin-1 beta and tumor necrosis factor-alpha induce MUC5AC overexpression through a mechanism involving ERK/p38 mitogen-activated protein kinases-MSK1-CREB activation in human airway epithelial cells. 1269 Jan 13

MUC2 mucin is a secretory glycoprotein which is produced from the intestinal goblet cells and is a major component of the intestinal epithelial mucus. The biological function of MUC2 mucin is considered to be the protection of intestinal epithelial surface, whereas the regulatory mechanism of MUC2 mucin production in immune response is not completely understood. We have studied the effects of cytokines, IL-4, IL-13 and TNF-alpha, on the regulation of MUC2 mRNA in the human colonic cancer cell lines, LS174T and HT29. The quantitative reverse transcription-polymerase chain reaction showed that single addition of IL-4, IL-13 and TNF-alpha to cell culture induced about two-fold increase of MUC2 mRNA level in LS174T cells. Interleukin-4 and IL-13 activated phosphorylation of mitogen-activated protein kinase in LS174T cells. A specific inhibitor of mitogen-activated protein kinase pathway, U0126, totally inhibited the increase of MUC2 mRNA by IL-4 or IL-13 in those cells. Therefore, mitogen-activated protein activation of kinase is required for the increase of MUC2 mRNA by IL-4 or IL-13 in LS174T cells. In contrast to LS174T cells, only TNF-alpha increased MUC2 mRNA through a mitogen-activated protein kinase pathway in HT29 cells that express low levels of MUC2 mRNA. These findings sustain a novel phenomenon that MUC2 mRNA expression is differently controlled by IL-4, IL-13, or TNF-alpha in LS174T and HT29 cells, whereas the mitogen-activated protein kinase pathway plays a role in the MUC2 mRNA expression induced by those cytokines in both cell lines.
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PMID:mRNA of MUC2 is stimulated by IL-4, IL-13 or TNF-alpha through a mitogen-activated protein kinase pathway in human colon cancer cells. 1284 48

Pretreatment of macrophages with Toll-like receptor (TLR)2 or TLR4 agonists leads to a stage of cell hyporesponsiveness to a second stimulation with TLR agonists. This tolerance state is accompanied by the repression of IL-1 receptor-associated kinase-1, mitogen-activated protein kinases, and IkappaB phosphorylation and expression of genes encoding proinflammatory cytokines, like IL-1beta and TNF-alpha. In this report, we demonstrated that mucin-like glycoprotein (tGPI-mucin) of Trypanosoma cruzi trypomastigotes (TLR2 agonist) and LPS (TLR4 agonist) induce cross-tolerance in macrophages and we addressed the role of phosphatase activity in this process. Analysis of the kinetic of phosphatase activity induced by tGPI-mucin or LPS revealed maximum levels between 12 and 24 h, which correlate with the macrophage hyporesponsiveness stage. The addition of okadaic acid, an inhibitor of phosphatase activity, reversed macrophage hyporesponsiveness after exposure to either LPS or tGPI-mucin, allowing phosphorylation of IL-1R-associated kinase-1, mitogen-activated protein kinases, and IkappaB and leading to TNF-alpha gene transcription and cytokine production. Furthermore, pretreatment with either the specific p38/stress-activated protein kinase-2 inhibitor (SB203580) or the NF-kappaB translocation inhibitor (SN50) prevented the induction of phosphatase activity and hyporesponsiveness in macrophage, permitting cytokine production after restimulation with LPS. These results indicate a critical role of p38/stress-activated protein kinase-2 and NF-kappaB-dependent phosphatase in macrophage hyporesponsiveness induced by microbial products that activate TLR2 and TLR4.
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PMID:Inhibition of a p38/stress-activated protein kinase-2-dependent phosphatase restores function of IL-1 receptor-associate kinase-1 and reverses Toll-like receptor 2- and 4-dependent tolerance of macrophages. 1287 38

Signaling molecules such as Cdc42 and mitogen-activated protein kinases (MAPKs) can function in multiple pathways in the same cell. Here, we propose one mechanism by which such factors may be directed to function in a particular pathway such that a specific response is elicited. Using genomic approaches, we identify a new component of the Cdc42- and MAPK-dependent signaling pathway that regulates filamentous growth (FG) in yeast. This factor, called Msb2, is a FG-pathway-specific factor that promotes differential activation of the MAPK for the FG pathway, Kss1. Msb2 is localized to polarized sites on the cell surface and interacts with Cdc42 and with the osmosensor for the high osmolarity glycerol response (HOG) pathway, Sho1. Msb2 is glycosylated and is a member of the mucin family, proteins that in mammalian cells promote disease resistance and contribute to metastasis in cancer cells. Remarkably, loss of the mucin domain of Msb2 causes hyperactivity of the FG pathway, demonstrating an inhibitory role for mucin domains in MAPK pathway activation. Taken together, our data suggest that Msb2 is a signaling mucin that interacts with general components, such as Cdc42 and Sho1, to promote their function in the FG pathway.
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PMID:A signaling mucin at the head of the Cdc42- and MAPK-dependent filamentous growth pathway in yeast. 1525 99

The trefoil factor family (TFF) peptides 1 and 2 (TFF1 and 2) are expressed in mucus cells of the stomach, whereas TFF3 is localized in goblet cells of the intestine. In the present study, we aimed to determine whether phosphatidylinositol 3-kinase (PI3-K) or signal transducer and activator of transcription protein 6 (STAT6) is involved in the expression of goblet cell specific markers. TFF3 expression was analyzed by RT-PCR, Northern blot, and radioimmunoassay (RIA) in relation to cell growth in subclones of HT-29 cells including the CL.16E and methotrexate (MTX) cell lines, which both exhibit a phenotype of mucus-secreting intestinal cells. A 30-fold increase in TFF3 mRNA levels and a 10-fold increase in TFF3-cell content were observed between the early proliferative and the late confluency states. The levels of MUC2 and MUC3 mRNA were also increased in the course of the differentiation process. A three to fourfold increase in PI3-K and Akt activities was observed in early post-confluent cells as compared with pre-confluent cells. Exposure of pre- and post-confluent cells to LY294002, a specific PI3-K inhibitor, for 1-4 days profoundly reduced TFF3 and MUC2 expression. A marked reduction in mucin granules content was also observed in LY-treated cells. Inhibition of the mitogen-activated protein (MAP) kinase kinase (MEK) with PD98059 did not modify the course of differentiation of the goblet cell lines. Moreover, stable transfection of HT-29 CL.16E cells with a dominant negative form of STAT6 had no effect on TFF3 induction. Together, these data indicate that PI3-K promotes the expression of TFF3 and MUC2 and that the PI3-K/Akt pathway may play a pivotal role in intestinal goblet cell differentiation.
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PMID:Expression of human TFF3 in relation to growth of HT-29 cell subpopulations: involvement of PI3-K but not STAT6. 1573 66

Airway mucus hypersecretion is now recognized as a key pathophysiological feature in many patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapies, including anticholinergics, ss2-adrenoceptor agonists, corticosteroids, mucolytics and macrolide antibiotics, have variable efficacy in inhibiting airway mucus hypersecretion, and are less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g. large conductance calcium-activated potassium, BKCa, channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g. benzafibrate), inhibitors of mucin exocytosis (e.g. anti-myristoylated alanine-rich C kinase substrate (MARCKS), peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g. epidermal growth factor (EGF), receptor tyrosine kinase inhibitors, p38 mitogen-activated protein (MAP), kinase inhibitors, MAP kinase kinase/extracellular signal-regulated kinase (MEK/ERK), inhibitors, human calcium-activated chloride (hCACL2), channel blockers and retinoic acid receptor-a antagonists), inducers of goblet cell apoptosis (e.g. Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify specific therapeutic targets which, in turn, should lead to rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma and COPD.
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PMID:Treatment of airway mucus hypersecretion. 1658 97


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