Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main etiologic factor for chronic bronchitis is cigarette smoke. Exposure to cigarette smoke is reported to induce goblet cell hyperplasia and mucus production. Mucin synthesis in airways has been reported to be regulated by the EGFR system. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the ligand-activated nuclear receptor superfamily. PPAR-gamma is implicated in anti-inflammatory responses, but mechanisms underlying these varied roles remain ill-defined. Recently, reports have shown that upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) might be one of the mechanisms through which PPAR-gamma agonists exert their anti-inflammatory actions. However, no data are available on the role of PPAR-gamma in smoke-induced mucin production. In this study, we investigated the effect of PPAR-gamma agonist (rosiglitazone) on smoke-induced mucin production in NCI-H292 cells. Exposure to cigarette smoke causes a significant decrease in PTEN expression and increases dose-dependent EGFR-specific tyrosine phosphorylation, resulting in MUC5AC mucin production in NCI-H292 cells. PPAR-gamma agonists or specific inhibitors of phosphoinositide 3-kinase exert inhibition of cigarette smoke-induced mucin production, with the upregulation of PTEN signaling and downregulation of Akt expression. This study demonstrates that PPAR-gamma agonist functions as a regulator of epithelial cell inflammation that may result in reduction of mucin-producing cells in airway epithelium.
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PMID:Peroxisome proliferator-activated receptor-gamma inhibits cigarette smoke solution-induced mucin production in human airway epithelial (NCI-H292) cells. 1644 43

MUC5AC is a secretory mucin normally expressed by the surface mucous cells of the human stomach and in the bronchial tract. It is absent from normal pancreas, but de novo expression of this mucin occurs in early-stage pancreatic intraepithelial neoplasias and in the invasive ductal adenocarcinoma of the pancreas, prompting this study of MUC5AC gene regulation in pancreatic cancer cells. Promoter deletion constructs and EMSA studies revealed that transcription factors Sp1 and AP-1 are both involved in basal transcription of the MUC5AC gene. Phorbol 12-myrisate 13-acetate (PMA) increased MUC5AC mRNA expression and transcriptional activities of MUC5AC promoter-reporter deletion constructs containing AP-1 consensus sites. EMSA studies showed that Fos/Jun binding to putative AP-1 sites is increased by PMA treatment. Western blot analysis showed that ERK, JNK and p38 are all activated by PMA treatment in SW1990 cells. Inhibitors of mitogen-activated protein/extracellular signal regulated kinase (MEK), such as ERK inhibitor PD98059 and JNK inhibitors dicumarol and SP60015, but not p38 inhibitor SB203580, inhibited PMA-induced MUC5AC reporter activity. Our studies indicate that Sp1 is involved in basal MUC5AC promoter activity while AP-1 is involved in basal and PMA-induced MUC5AC promoter activation in pancreatic cancer cells. Furthermore, PMA-induced MUC5AC gene transcription appears to be mediated by activating Sp1, PKC/ERK/AP-1 and PKC/JNK/AP-1 pathways.
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PMID:MUC5AC mucin gene regulation in pancreatic cancer cells. 1677 82

A 44-year-old man was referred for a right chest nodule of 3 months duration. A 'benign' nodule had been excised from this location 8 years prior. On examination, palpable nodes were noted in the right axilla. Radiographic studies were significant only for right axillary lymphadenopathy. Histologically, a nodular dermal proliferation composed of poorly differentiated epithelioid cells in nests and focally forming ducts with pseudopapillary architecture comprised the primary tumor. Features of a clear cell hidradenoma were noted focally. Immunohistochemical (IHC) analysis revealed reactivity for HMW cytokeratins, CK5 and CK7, p53, p63, CEA (focal), androgen receptor, EGFR, estrogen receptor (ER), MUC5AC, and strong/diffuse membranous staining for Her-2/neu. Negative stains included villin, TTF-1, CDX2, S-100 protein, vimentin, gross cystic disease fluid protein 15 (GCDFP-15), mammoglobulin, and MUC2. A wide local excision and axillary node dissection was performed. Metastatic tumor involved nine of 28 nodes. Interphase fluorescence in situ hybridization (FISH) demonstrated chromosomal amplification of the Her-2/neu locus within the tumor and a nodal metastasis. The patient has completed adjuvant and radiotherapy, including trastuzumab, and is asymptomatic. We believe this to be the first demonstration of Her-2/neu amplification in a malignant skin adnexal tumor. In analogy to breast carcinoma, these findings suggest the applicability of trastuzumab for patients with metastatic adnexal carcinomas demonstrating Her-2/neu amplification.
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PMID:Metastatic hidradenocarcinoma with demonstration of Her-2/neu gene amplification by fluorescence in situ hybridization: potential treatment implications. 1721 55

Epithelial cells represent the first line of host innate defense against invading microbes by elaborating a range of molecules involved in pathogen clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. How mucin is induced in upper respiratory Streptococcus pneumoniae infections is unknown. In this study, we show that pneumolysin is required for up-regulation of MUC5AC mucin via TLR4-dependent activation of ERK in human epithelial cells in vitro and in mice in vivo. Interestingly, a "second wave" of ERK activation appears to be important in mediating MUC5AC induction. Moreover, IkappaB kinase (IKK) alpha and IKKbeta are distinctly involved in MUC5AC induction via an ERK1-dependent, but IkappaBalpha-p65- and p100-p52-independent, mechanism, thereby revealing novel roles for IKKs in mediating up-regulation of MUC5AC mucin by S. pneumoniae.
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PMID:A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae. 1723 23

Mucin, a major component of mucus, plays a critical role in host mucosal defense response by participating in mucociliary clearance. However, if overproduced, overproduced mucus leads to airway mucus obstruction and conductive hearing loss. Despite extensive studies that focus on investigating how MUC5AC mucin is regulated by one inducer at a time, how MUC5AC is synergistically regulated by multiple factors remains unknown. Here we provide direct evidence for the first time that bacterial pathogen NTHi and human growth factor EGF synergize with each other to potently up-regulate MUC5AC mucin transcription. Moreover, activation of both p38 and ERK is required for synergistic induction of MUC5AC by NTHi and EGF. Finally, PAK2 and PAK4 are differentially involved in this synergistic induction of MUC5AC by acting upstream of p38 and ERK. Our studies bring novel insights into our understanding of synergistic regulation of MUC5AC mucin by both pathological and physiological inducers.
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PMID:Opposing roles of PAK2 and PAK4 in synergistic induction of MUC5AC mucin by bacterium NTHi and EGF. 1755 15

The EGFR plays an essential role in goblet cell hyperplasia and mucus hypersecretion. EGFR has an intrinsic tyrosine kinase activity that, when activated, induces the production of MUC5AC through the signaling kinase cascade in the airway epithelium. We have investigated the effects of an EGFR tyrosine kinase inhibitor, gefitinib, on ovalbumin (OVA)-induced, allergic inflammation in airway epithelia of mice. OVA-sensitized mice were pretreated with gefitinib at two different doses (12.5 and 50 mg/kg) and then challenged with OVA. The OVA challenge increased the total cell count and eosinophil count in bronchoalveolar lavage fluid (BALF), as well as the concentrations of T-helper2 (Th2) cytokines, such as IL-4 and IL-13, overall eosinophil recruitment in the lung tissue and airway hyperresponsiveness (AHR). Pretreatment with gefitinib reduced the inflammatory cell counts and released cytokine concentrations (IL-4 and IL-13) in BALF, as well as eosinophil recruitment in the lungs and AHR, in a dose-dependent manner. This was associated with decreased EGFR and Akt phosphorylation. We showed that gefinitib inhibits EGFR and phosphoinositol 3'-kinase (PI3K)/Akt activation which were activated in OVA sensitized mice. These findings suggest that inhibitors of the EGFR cascade may have a role in the treatment of asthma.
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PMID:Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation. 1760 91

The gel-forming MUC5AC and MUC5B mucins have been identified as major components of human airway mucus but it is not known whether additional mucin species, possibly with other functions, are also present. MUC16 mucin is a well-known serum marker for ovarian cancer, but the molecule has also been found on the ocular surface and in cervical secretions suggesting that it may play a role on the normal mucosal surface. In this investigation, the LUM16-2 antiserum (raised against a sequence in the N-terminal repeat domain) recognized MUC16 in goblet and submucosal gland mucous cells as well as on the epithelial surface of human tracheal tissue suggesting that the mucin originates from secretory cells. MUC16 mucin was present in 'normal' respiratory tract mucus as well as in secretions from normal human bronchial epithelial (NHBE) cells. MUC16 from NHBE cells was a high-molecular-mass, monomeric mucin which gave rise to large glycopeptides after proteolysis. N- and C-terminal fragments of the molecule were separated on gel electrophoresis showing that the MUC16 apoprotein undergoes a cleavage between these domains, possibly in the SEA domain as demonstrated for other transmembrane mucins; MUC1 and MUC3. After metabolic labeling of NHBE cells, most of the secreted monomeric, high-molecular-mass [(35)S]sulphate-labelled molecules were immunoprecipitated with the OC125 antibody indicating that MUC16 is the major [(35)S]sulphate-labelled mucin in NHBE cell secretions.
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PMID:MUC16 is produced in tracheal surface epithelium and submucosal glands and is present in secretions from normal human airway and cultured bronchial epithelial cells. 1760 78

Mucin overproduction is a hallmark of chronic respiratory diseases (CRD) such as chronic obstructive pulmonary disease and asthma, and otitis media. Despite the fact that nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae are co-existing under these disease conditions, little is known about how NTHi and S. pneumoniae induce mucin overproduction. Here we show that NTHi and S. pneumoniae, when present together, synergistically induce MUC5AC mucin transcription. TLR2/4-MyD88-TAK1 signaling cascade transmits signal to regulate the synergistic induction of MUC5AC. The activation of MKK3/6-p38 and ERK MAPK pathways are required for the synergistic induction of MUC5AC. Moreover, S. pneumoniae synergizes with NTHi to induce MUC5AC expression via AP-1-dependent mechanism. Thus, our studies provide direct evidence for the synergistic induction of MUC5AC in mixed infections and bring novel insights into our understanding of molecular mechanisms underlying polymicrobial infections in CRD and OM.
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PMID:Synergistic induction of MUC5AC mucin by nontypeable Haemophilus influenzae and Streptococcus pneumoniae. 1803 71

It has been reported that the proinflammatory cytokine interleukin-1beta (IL-1beta) induces mucus hypersecretion in normal human nasal epithelial (NHNE) cells and that the MAP kinase pathway may be an important signal pathway in IL-1beta-induced MUC5AC gene expression. Green tea (Camellia sinensis) polyphenols are potent anti-inflammatory agents and have been shown to inhibit inflammation in tumor cell lines and cultured respiratory epithelial cells. In this study, we examined the effect of (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol, on IL-1beta-induced MUC5AC gene expression and secretion in NHNE cells. After cells had been treated with IL-1beta (10 ng/ml) and pretreated with EGCG (10, 50 and 100 microM), mRNA expression of MUC5AC was determined by real-time polymerase chain reaction. The suppression of each signal pathway protein was determined by Western blot analysis after treatment with IL-1beta and EGCG, respectively. IL-1beta increased MUC5AC gene expression and MUC5AC secretion. EGCG markedly suppressed IL-1beta-induced MUC5AC gene expression and MUC5AC secretion via suppression of the phosphorylation of ERK MAP kinase, MSK1, and transcription factor, cAMP response element-binding protein. IL-1beta increased the number of cells staining positive with MUC5AC antibodies, and EGCG treatment decreased this number. Our data suggest that EGCG may be an effective inhibitor of IL-1beta-induced mucus hypersecretion.
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PMID:Epigallocatechin-3-gallate inhibits interleukin-1beta-induced MUC5AC gene expression and MUC5AC secretion in normal human nasal epithelial cells. 1815 12

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


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