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)

TIM (T cell, Ig, mucin) proteins can regulate T cell immune responses. Tim-4 mRNA is not expressed in T cells, but exclusively in APCs. Tim-4 is a ligand for Tim-1 and Tim-4.Ig fusion protein was shown to either inhibit or expand T cells. However, the molecular basis for such opposite effects was not defined. By generating mAbs, we show that expression of Tim-4 protein is restricted to CD11c(+) and CD11b(+) cells and is up-regulated upon activation. We show that Tim-4 specifically phosphorylates Tim-1 and induces T cell expansion by enhancing cell division and reducing apoptosis. Tim-4 also induces the phosphorylation of signaling molecules LAT, Akt, and ERK1/2 in T cells. Tim-4, expressed on APCs, is a costimulatory molecule that promotes T cell expansion and survival by cross-linking Tim-1 on T cells.
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PMID:TIM-4 expressed on APCs induces T cell expansion and survival. 1835 94

Mucus hypersecretion is a prominent manifestation in patients with chronic inflammatory airway diseases, and MUC5AC is a major airway mucin. It is well known that reactive oxygen species (ROS) may be involved in the pathogenesis of various inflammatory airway diseases. The purpose of this study was to identify which secreted mucin genes are induced by exogenous hydrogen peroxide and the mechanism by which these genes are up-regulated in normal human nasal epithelial (NHNE) cells. Exogenous H(2)O(2) induced the ligand-independent activation of epidermal growth factor receptors (EGFR) and the subsequent activation of ERK1 mitogen-activated protein kinase, resulting in the induction of intracellular ROS generation. Through this signal pathway, exogenous H(2)O(2) markedly induced overexpression of the MUC5AC gene alone. In addition, Nox4, a subtype of nonphagocytic NADPH oxidase, was found to play a key role in intracellular ROS generation and exogenous H(2)O(2)-induced MUC5AC gene expression in NHNE cells.
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PMID:The role of Nox4 in oxidative stress-induced MUC5AC overexpression in human airway epithelial cells. 1853 55

Fudosteine is a novel mucoactive agent, although little is known about how fudosteine decreases mucin production. The present study examined the effects of fudosteine on MUC5AC mucin synthesis and cellular signalling. An animal model of lipopolysaccharide (LPS)-induced inflammation and a bronchial epithelial cell line model of tumour necrosis factor (TNF)-alpha-induced inflammation were used. Fudosteine was administered before stimulation with LPS or TNF-alpha. The MUC5AC mucin levels were assayed and the expression of the MUC5AC gene was measured. Western blotting was carried out for the detection of phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and phosphorylated extracellular signal-related kinase (p-ERK). MUC5AC mucin synthesis and the expression of the MUC5AC gene were increased by LPS in rats or TNF-alpha in NCI-H292 cells; these effects were inhibited by fudosteine treatment. After stimulation with LPS or TNF-alpha, the expression of p-EGFR, p-p38 MAPK and p-ERK were detected. Fudosteine treatment reduced the expression levels of p-p38 MAPK and p-ERK in vivo and of p-ERK in vitro. The present results suggest fudosteine inhibits MUC5AC mucin hypersecretion by reducing MUC5AC gene expression and the effects of fudosteine are associated with the inhibition of extracellular signal-related kinase and p38 mitogen-activated protein kinase in vivo and extracellular signal-related kinase in vitro.
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PMID:Effect of fudosteine on mucin production. 1905 87

Signaling mucins are cell adhesion molecules that activate RAS/RHO guanosine triphosphatases and their effector mitogen-activated protein kinase (MAPK) pathways. We found that the Saccharomyces cerevisiae mucin Msb2p, which functions at the head of the Cdc42p-dependent MAPK pathway that controls filamentous growth, is processed into secreted and cell-associated forms. Cleavage of the extracellular inhibitory domain of Msb2p by the aspartyl protease Yps1p generated the active form of the protein by a mechanism incorporating cellular nutritional status. Activated Msb2p functioned through the tetraspan protein Sho1p to induce MAPK activation as well as cell polarization, which involved the Cdc42p guanine nucleotide exchange factor Cdc24p. We postulate that cleavage-dependent activation is a general feature of signaling mucins, which brings to light a novel regulatory aspect of this class of signaling adhesion molecule.
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PMID:Cleavage of the signaling mucin Msb2 by the aspartyl protease Yps1 is required for MAPK activation in yeast. 1859 27

MUC5B is a major mucin of the human respiratory tract, and it is not clear how MUC5B expression is regulated in various airway diseases. The goal of this study was to determine the mechanisms by which 17beta-estradiol induces MUC5B gene expression in airway epithelial cells. It was found that E2, a sex hormone, stimulates MUC5B gene overexpression by interaction with estrogen receptor alpha (ERalpha) and by acting through extracellular signal-regulated kinase 1/2 (ERK1/2)-mitogen-activated protein kinase (MAPK). Pretreatment with ER antagonist ICI 182,780 blocked both E2-induced ERK1/2-MAPK activation and MUC5B gene expression. It was also found that the activation of p90 ribosomal S 6 protein kinase 1 (RSK1), cAMP-response element-binding protein (CREB), and cAMP-response element (CRE) (-956 region of the MUC5B promoter)-responsive signaling cascades via ERK1/2 MAPK are crucial aspects of the intracellular mechanisms that mediate MUC5B gene expression. Taken together, these studies give additional insights into the molecular mechanism of hormone-induced MUC5B gene expression and enhance our understanding of abnormal mucin secretion in response to hormonal imbalances.
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PMID:Signal pathway of 17beta-estradiol-induced MUC5B expression in human airway epithelial cells. 1868 42

Mucus hypersecretion with elevated MUC5B mucin production is a pathologic feature in many airway diseases associated with oxidative stress. In the present work, we evaluated MUC5B expression in airways and in primary cultures of normal human bronchial epithelial (NHBE) cells, as well as the mechanisms involved in its regulation. We found that oxidative stress generated by cigarette smoke or reactive oxygen species (ROS) induces MUC5B up-regulation in airway epithelium from smokers and in NHBE cells, respectively. We have previously shown that ROS-induced MUC5AC expression in NHBE cells is dependent on hyaluronan depolymerization and epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) activation. Since hyaluronan fragments can activate MAPK through the hyaluronan receptor CD44, and CD44 heterodimerizes with EGFR, we tested whether ROS and/or hyaluronan fragments induce MUC5B mRNA and protein expression through CD44/EGFR. We found that ROS promotes CD44/EGFR interaction, EGFR/MAPK activation, and MUC5B up-regulation that are prevented by blocking CD44 and/or EGFR. These results were mimicked by hyaluronan fragments. In summary, our results show that oxidative stress in vivo (cigarette smoke) or in vitro (ROS) induces MUC5B up-regulation. This ROS-induced MUC5B expression requires CD44 as well as EGFR and MAPK activation. In addition, we also provide evidence that hyaluronan fragments are sufficient to induce CD44/EGFR interaction and downstream signaling that results in MUC5B up-regulation, suggesting that hyaluronan depolymerization during inflammatory responses could be directly involved in the induction of mucus hypersecretion.
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PMID:Hyaluronan fragments/CD44 mediate oxidative stress-induced MUC5B up-regulation in airway epithelium. 1875 7

Mucosal epithelial cells in the respiratory tract act as the first line of host innate defense against inhaled microbes by producing a range of molecules for clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping the inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. Excess mucin production, however, overwhelms the mucociliary clearance, resulting in defective mucosal defenses. Thus, tight regulation of mucin production is critical for maintaining an appropriate balance between beneficial and detrimental outcomes. Among various mechanisms, negative regulation plays an important role in tightly regulating mucin production. Here we show that the PAK4-JNK signaling pathway acted as a negative regulator for Streptococcus pneumoniae pneumolysin-induced MUC5AC mucin transcription. Moreover pneumolysin also selectively induced expression of MKP1 via a TLR4-dependent MyD88-TRAF6-ERK signaling pathway, which inhibited the PAK4-JNK signaling pathway, thereby leading to up-regulation of MUC5AC mucin production to maintain effective mucosal protection against S. pneumoniae infection. These studies provide novel insights into the molecular mechanisms underlying the tight regulation of mucin overproduction in the pathogenesis of airway infectious diseases and may lead to development of new therapeutic strategies.
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PMID:MKP1 regulates the induction of MUC5AC mucin by Streptococcus pneumoniae pneumolysin by inhibiting the PAK4-JNK signaling pathway. 1878 68

Glucocorticoids are highly effective in the control of many inflammatory and immune diseases. Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, the molecular basis for the inhibitory effect of glucocorticoids on mucin overproduction, a hallmark of chronic respiratory diseases, still remains unclear. Here we show that glucocorticoids markedly inhibit up-regulation of MUC5AC induced by NTHi, a major human bacterial pathogen causing chronic obstructive pulmonary disease and otitis media. Inhibition of NTHi-induced MUC5AC expression by dexamethasone occurs at the level of p38 MAPK via glucocorticoid receptor. Moreover, glucocorticoids up-regulate MKP-1 expression, which in turn leads to p38 dephosphorylation and the subsequent inhibition of NTHi-induced MUC5AC expression. These studies provide new insight into the molecular mechanism underlying glucocorticoid therapy and may lead to novel therapeutic intervention for inhibiting mucin overproduction in patients with NTHi infections.
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PMID:Glucocorticoids inhibit nontypeable Haemophilus influenzae-induced MUC5AC mucin expression via MAPK phosphatase-1-dependent inhibition of p38 MAPK. 1895 83

Viral infection is a major trigger for exacerbation of asthma and induces overproduction of mucins. We investigated whether dsRNA could amplify the induction of mucin by TGF-alpha in human bronchial epithelial cells, as well as the molecular mechanisms regulating MUC5AC expression. Human pulmonary mucoepidermoid carcinoma (NCI-H292) cells and normal human bronchial epithelial cells were exposed to polyinosinic-cytidyric acid (poly(I:C)) and TGF-alpha. Then, MUC5AC protein production, mRNA expression, and promoter activity were evaluated. Cells were pretreated with a selective inhibitor of ERK, and phosphorylation of ERK was examined by Western blotting. Furthermore, the expression of MAPK phosphatase 3 (MKP3) mRNA was evaluated and the effect of MKP3 overexpression was assessed. Poly(I:C) synergistically increased MUC5AC induction by TGF-alpha in both NCI-H292 and normal human bronchial epithelial cells. This increase was dependent on MUC5AC gene transcription. A MEK1/2 inhibitor (U0126) significantly inhibited MUC5AC production. Phosphorylation of ERK was enhanced by poly(I:C). TGF-alpha stimulation up-regulated MKP3 mRNA expression, while costimulation with poly(I:C) inhibited this up-regulation dose-dependently. Enhanced expression of MUC5AC mRNA by poly(I:C) in wild-type cells was completely suppressed in cells transfected with the MKP3 expression vector. dsRNA can synergistically amplify the induction of MUC5AC mucin by TGF-alpha. This synergistic effect on MUC5AC production may be due to enhanced activation of ERK through inhibition of MKP3 by poly(I:C).
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PMID:Double-stranded RNA and TGF-alpha promote MUC5AC induction in respiratory cells. 1910 60

Acute lung injury represents the result of multiple pathways initiated by local or systemic insults and is characterized by profound vascular permeability, pulmonary edema, and life-threatening respiratory failure. Permeability-reducing therapies are of potential clinical utility but are currently unavailable. We hypothesized that polyethylene glycol (PEG) compounds, inert and non-toxic polymers that serve as a surrogate mucin lining in intestinal epithelium, may attenuate agonist-mediated lung endothelial cell (EC) barrier dysfunction. High molecular weight PEG (PEG15-20) produced rapid, dose-dependent increases in transendothelial electrical resistance (TER) in human lung endothelium cultured on gold microelectrodes, reflecting increased paracellular integrity. The maximal effective concentration of 8% PEG induced a sustained 125% increase in TER (40 h), results similar to barrier-enhancing agonists such as sphingosine 1-phosphate (40% increase in TER). Maximal PEG barrier enhancement was achieved at 45-60 min and PEG effectively reversed both thrombin- and LPS-induced EC barrier dysfunction. Consistent with the increase in TER, immunofluorescent studies demonstrated that PEG produced significant cytoskeletal rearrangement with formation of well-defined cortical actin rings and lamellipodia containing the actin-binding proteins, cortactin and MLCK, known participants in cell-matrix and cell-cell junctional adhesion. Finally, PEG challenge induced rapid alterations in levels of MAP kinase and MLC phosphorylation. In summary, PEG joins a number of EC barrier-regulatory agents which rapidly activate barrier-enhancing signal transduction pathways which target the cytoskeleton and provides a potential therapeutic strategy in inflammatory lung injury.
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PMID:Protective effects of high-molecular weight polyethylene glycol (PEG) in human lung endothelial cell barrier regulation: role of actin cytoskeletal rearrangement. 1912 27


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