Flowchart: Preparation: Muc5acc
Text Box: Ras
Text Box: Pma
 

 


Nitric oxide

 

Text Box: Muc5B

Text Box: Muc5ac

Asthma

COPD

Cystic Fibrosis

 

Text Box:   Pkc-alphaText Box: TNF-alpha 

Text Box: Pkc-delta 

 

 

2008/6/22-39

 

 Am J Pathol. 2007 Jan;170(1):20-32.Click here to read  Links

Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate.

     Yuan-Chen Wu D, Wu R, Reddy SP, Lee YC, Chang MM.

Center for Comparative Respiratory Biology and Medicine, Genome and Biomedical Science Facility, Suite 6510 University of California, Davis, 451 East Health Sciences Dr., Davis, CA 95616, USA.

Elevated expression of gel-forming mucin (MUC) genes MUC5AC and MUC5B is a major pathological feature in various airway diseases. In this study, we show that phorbol 12-myristate 13-acetate (PMA) is a potent stimulator for MUC5B gene expression under air-liquid interface conditions in three airway epithelial cell systems: primary cultures of normal human bronchial epithelial cells, the immortalized normal bronchial epithelial cell line HBE1, and the human lung adenocarcinoma cell line A549. Stimulation was time- and dose-dependent, could be demonstrated by promoter-reporter gene transfection, and was sensitive to mithramycin A, suggesting the involvement of a specificity protein 1-based transcriptional mechanism in the stimulation. PMA-induced MUC5B message and promoter-reporter gene activity were specifically sensitive to inhibition of protein kinase C delta, which was further confirmed by the forced expression of dominant-negative mutant of protein kinase C delta. Regarding downstream transduction, PMA-induced MUC5B expression was sensitive to inhibitors and dominant-negative expression of signaling molecules involved in Ras/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase1-mediated c-Jun N-terminal kinase and p38 pathways. This contrasted with the inhibition of PMA-induced MUC5AC expression by inhibitors of the Ras/epidermal growth factor receptor/extracellular regulated kinase signaling pathway. These results demonstrate for the first time that PMA-stimulated MUC5AC and MUC5B expressions are regulated through distinctive epidermal growth factor receptor/extracellular regulated kinase-dependent and -independent signaling pathways.

Am J Respir Crit Care Med. 2007 Apr 15;175(8):816-21. Epub 2007 Jan 25.Click here to read Links

MUC5AC and MUC5B mucins increase in cystic fibrosis airway secretions during pulmonary exacerbation.

Henke MO, John G, Germann M, Lindemann H, Rubin BK.

Philipps-University Marburg, Department of Pulmonary Medicine, Baldingerstrasse 1, 35043 Marburg, Germany. markus.henke@staff.uni-marburg.de.

RATIONALE: Cystic fibrosis (CF) is believed to be associated with mucus hypersecretion; thus, the principal airway gel-forming mucins, MUC5AC and MUC5B, are also expected to be increased relative to non-CF secretions. However, we have shown that these mucins are decreased during stable CF disease. OBJECTIVES: In this study, we determine if these mucins increase during a pulmonary exacerbation of CF. METHODS: Expectorated sputum was collected from 11 adults with CF during stable disease and then during a pulmonary exacerbation and from 12 healthy control subjects. MUC5AC and MUC5B proteins were measured by Western blot. DNA content was measured using microfluorimetry. RESULTS: MUC5AC protein increased by 908% and MUC5B by 59% (p < 0.05 for both) during an exacerbation compared with periods of stable disease. During stable disease, the vol/vol quantity of MUC5AC protein was 89% less than normal mucus, and the mucin-associated sugars, measured using a lectin binding assay, were 46% less compared with normal mucus. The concentration of DNA in CF sputum did not increase during an exacerbation. CONCLUSIONS: During a CF exacerbation, concentration of secreted mucin increased to the amount found in mucus from normal subjects, suggesting that the capacity to secrete mucin in response to an infection or inflammatory stimulus is preserved in CF airways. This might help to protect the airway from injury.

PMID: 17255563 [PubMed - indexed for MEDLINE]

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Respir Res. 2007 Mar 29;8:28.Click here to read Click here to read  Links

Nitric oxide induces MUC5AC mucin in respiratory epithelial cells through PKC and ERK dependent pathways.

     Song JS, Kang CM, Yoo MB, Kim SJ,Yoon

HK Kim YK, Kim KH, Moon HS, Park SH.

Department of Internal Medicine, St Mary's hospital, Catholic University Medical College, Yeoi-Do Dong, Young Dung Po Gu, Seoul, Korea. jssong@catholic.ac.kr

BACKGROUND: Nitric oxide (NO) is generally increased during inflammatory airway diseases. This increased NO stimulates the secretion of mucin from the goblet cell and submucosal glands but the mechanism is still unknown precisely. In this study, we investigated potential signaling pathways involving protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) in the NO-induced MUC5AC mucin gene and protein expression in A549 cells. METHODS: Nitric oxide was donated to the A549 cells by NOR-1. MUC5AC mucin levels were assayed by enzyme-linked immunosorbent assay (ELISA). MUC5AC promoter activity was determined by measuring luciferase activity after the lysing the transfected cells. Activation of PKC isoforms were measured by assessing the distribution of the enzyme between cytosolic and membrane fractions using immunoblotting. Immunoblotting experiments using a monoclonal antibody specific to PKC isoforms were performed in the cytosol and membrane fractions from A549 cells. Western blot analysis for pERK and p38 were performed using the corresponding antibodies from the cell lysates after donating NO to the A549 cells by NOR-1. RESULTS: The transcriptional activity of MUC5AC promoter was maximal at the concentration of 0.1 mM NOR-1 for 1 hour incubation in transfected A549 cells. (+/-)-(E)-methyl-2-((E)-hydroxyimino)-5-nitro-6-methoxy-3-hexenamide (NOR-1) markedly displaced the protein kinase C (PKC)alpha and PKCdelta from the cytosol to the membrane. Furthermore, the PKC-alpha,betainhibitors, GO6976 (10 nM) and PKCdelta inhibitors, rottlerin (4 muM) inhibited the NOR-1 induced migration of PKCalpha and PKCdelta respectively. NOR-1 also markedly increased the MUC5AC promoter activity and mRNA expression, mucin synthesis and ERK1/2 phosphorylation. The PKC inhibitors also inhibited the NOR-1 induced MUC5AC mRNA and MUC5AC protein synthesis by inhibiting the activation of PKCalpha and PKCdelta with ERK1/2 pathways. CONCLUSION: Exogenous NO induced the MUC5AC mucin gene and protein through the PKCalpha and PKCdelta-ERK pathways in A549 cells. Inhibition of PKC attenuated NO-mediated MUC5AC mucin synthesis. In view of this findings, PKC inhibitors might be useful in the treatment of bronchial asthma and chronic bronchitis patients where NO and mucus are increased in the bronchial airways.

PMID: 17391532 [PubMed - indexed for MEDLINE]

Am J Respir Cell Mol Biol. 2006 Aug;35(2):165-74. Epub 2006 Mar 16.Click here to read  Links

     Baginski TK, Dabbagh K, Satjawatcharaphong C, Swinney DC.

Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.

Pathogenic factors associated with chronic obstructive pulmonary disease (COPD), such as cigarette smoke, proinflammatory cytokines, and bacterial infections, can individually induce respiratory mucins in vitro and in vivo. Since co-presence of these factors is common in lungs of patients with COPD, we hypothesized that cigarette smoke can amplify mucin induction by bacterial exoproducts and proinflammatory cytokines, resulting in mucin hyperproduction. We demonstrated that cigarette smoke extract (CSE) synergistically increased gene expression and protein production of MUC5AC mucin induced by LPS or TNF-alpha in human airway epithelial NCI-H292 cells. CSE also enhanced expression and production of MUC5AC mucin induced by epidermal growth factor receptor (EGFR) ligands TGF-alpha and amphiregulin, as well as LPS- and TNF-alpha- induced expression and/or release of TGF-alpha and amphiregulin. Furthermore, (4-[(3-bromophenyl)amino]-6,7-diaminoquinazoline), a potent inhibitor of EGFR, blocked synergistic induction of MUC5AC mucin. H(2)O(2) mimicked the synergistic effects of CSE, while antioxidant N-acetyl-L-cysteine prevented synergistic induction of MUC5AC mucin by CSE. In a rat model of LPS-induced airway inflammation, concurrent cigarette smoke inhalation enhanced mucin content of the bronchoalveolar lavage fluid, muc5AC gene expression, and mucous cell metaplasia in the airways. These results suggest that cigarette smoke has the potential to synergistically amplify induction of respiratory mucins by proinflammatory stimuli relevant to COPD pathogenesis and contribute to mucin hyperproduction observed in patients with COPD.

PMID: 16543607 [PubMed - indexed for MEDLINE]