PT - JOURNAL ARTICLE AU - Hai Feng Ou Yang TI - Notch signaling negatively regulate the expression of MUC5AC in airway goblet cells DP - 2012 Sep 01 TA - European Respiratory Journal PG - P3405 VI - 40 IP - Suppl 56 4099 - http://erj.ersjournals.com/content/40/Suppl_56/P3405.short 4100 - http://erj.ersjournals.com/content/40/Suppl_56/P3405.full SO - Eur Respir J2012 Sep 01; 40 AB - Introduction and background: Goblet cell metaplasia and airway mucus hypersecretion contributed to the pathogenesis of asthma and COPD. Evidence has shown that Notch signaling modulates the development of lung epithelial and the differentiation of intestinal goblet cells. Whether Notch signaling can regulate the expression of MUC5AC, a major component of airway mucus, is still unknown. Aim and objective: To investigate whether Notch signaling can regulate MUC5AC expression in airway goblet cells. Methods: Expression of Notch receptors and downstream molecules in airway goblet cells was examined. Then, after transfected with pEFBOS-NIC (upregulating Notch signaling) or treated with γ-secretase inhibitor (downregulating Notch signaling), the MUC5AC expression in airway goblet cells was examined. Finally, the transcriptional regulatory mechanisms were analyzed. Results: Airway goblet cells express Notch1, Notch3 and downstream transcription factor hes1. Notch signaling can modulate the MUC5AC expression both in vivo and in vitro. Two N-box sites (hes1 binding site), -1439 and -893, were identified within mouse MUC5AC promoter. One N-box site (-293) was identified within human MUC5AC promoter. The Notch intracellular domain NIC, the active form of Notch receptors, activates the reporters driven by mouse or human MUC5AC promoters. Site-directed mutagenesis reporter assays confirmed that mouse N-box (-893) and human N-box (-293) negatively regulated MUC5AC promoter activity. ChIP assays showed that Hes1 bound to the MUC5AC promoter in both mouse and human airway goblet cells. Conclusions: Notch signaling negatively regulates the MUC5AC expression through Hes1-dependent mechanism in airway goblet cells.