表皮生长因子受体
信号转导
粘蛋白
癌症研究
PI3K/AKT/mTOR通路
安非雷古林
MAPK/ERK通路
激酶
吉非替尼
化学
表皮生长因子
蛋白激酶B
细胞生物学
磷酸化
缺氧诱导因子
受体
生物
生物化学
基因
作者
Hongyang Yu,Qi Li,Victor P. Кolosov,Juliy M. Perelman,Xiangdong Zhou
摘要
ABSTRACT Cigarette smoking is strongly implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Mucus hypersecretion is the key manifestation in patients with COPD and mucin 5AC (MUC5AC) is a major component of airway mucus. Hypoxia inducible factor‐1 (HIF‐1) is a transcriptional factor which can be stimulated to bind to the MUC5AC promoter and induce MUC5AC promoter activation. Previous studies have reported that activation of HIF‐1 α pathways by cigarette smoke contributes to the development of COPD. We hypothesize that cigarette smoke up‐regulates HIF‐1 α production and HIF‐1 activity through epidermal growth factor receptor (EGFR)‐activated signal cascades pathways, leading to mucin production in human airway epithelial cells (16HBE). We show that cigarette smoke increases HIF‐1 α production, HIF‐1 activity and MUC5AC expression. These effects are prevented by small interfering RNA (siRNA) for HIF‐1 α , indicating that cigarette smoke‐induced mucin production is HIF‐1 α ‐dependent. Cigarette smoke activates extracellular signal‐regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3‐kinase (PI3K) signal pathways, both of which are inhibited by gefitinib (an inhibitor of EGFR), suggesting that cigarette smoke‐activated signal pathways are mediated by EGFR in 16HBE cells. Furthermore, pretreatment with gefitinib and the pharmacological inhibitors of PI3K (LY294002) and ERK1/2 (PD98059) prevented cigarette smoke‐mediated Akt and ERK1/2 phosphorylation responses, HIF‐1 α production, HIF‐1 activity and MUC5AC expression. These observations demonstrate an important role for EGFR‐mediated signaling pathways in regulating cigarette smoke‐induced HIF‐1 activation and MUC5AC expression. Our results suggest that cigarette smoke activates EGFR‐mediated signaling pathways, leading to HIF‐1 α production and HIF‐1 activation, resulting in mucin expression in human airway epithelial cells. Copyright © 2011 John Wiley & Sons, Ltd.
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