PMID- 21544845
OWN - NLM
STAT- MEDLINE
DCOM- 20120618
LR  - 20231213
IS  - 1099-1263 (Electronic)
IS  - 0260-437X (Linking)
VI  - 32
IP  - 4
DP  - 2012 Apr
TI  - Regulation of cigarette smoke-mediated mucin expression by hypoxia-inducible 
      factor-1alpha via epidermal growth factor receptor-mediated signaling pathways.
PG  - 282-92
LID - 10.1002/jat.1679 [doi]
AB  - 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-1alpha pathways by 
      cigarette smoke contributes to the development of COPD. We hypothesize that 
      cigarette smoke up-regulates HIF-1alpha 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-1alpha production, HIF-1 activity and MUC5AC 
      expression. These effects are prevented by small interfering RNA (siRNA) for 
      HIF-1alpha, indicating that cigarette smoke-induced mucin production is 
      HIF-1alpha-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-1alpha 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-1alpha production and HIF-1 
      activation, resulting in mucin expression in human airway epithelial cells.
CI  - Copyright (c) 2011 John Wiley & Sons, Ltd.
FAU - Yu, Hongmei
AU  - Yu H
AD  - Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical 
      University, No. 74, Linjiang Road, Yuzhong District, Chongqing, 400010, China.
FAU - Li, Qi
AU  - Li Q
FAU - Kolosov, Victor P
AU  - Kolosov VP
FAU - Perelman, Juliy M
AU  - Perelman JM
FAU - Zhou, Xiangdong
AU  - Zhou X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110504
PL  - England
TA  - J Appl Toxicol
JT  - Journal of applied toxicology : JAT
JID - 8109495
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Mucin 5AC)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Smoke)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Cells, Cultured
MH  - Epithelial Cells/metabolism
MH  - ErbB Receptors/genetics/*metabolism
MH  - Gefitinib
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Mitogen-Activated Protein Kinase 3/antagonists & inhibitors/genetics/metabolism
MH  - Mucin 5AC/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinase/genetics/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Quinazolines/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - *Signal Transduction
MH  - Smoke/analysis
MH  - Smoking/*adverse effects
MH  - Nicotiana
MH  - Up-Regulation
EDAT- 2011/05/06 06:00
MHDA- 2012/06/19 06:00
CRDT- 2011/05/06 06:00
PHST- 2010/09/26 00:00 [received]
PHST- 2011/01/04 00:00 [revised]
PHST- 2011/02/04 00:00 [accepted]
PHST- 2011/05/06 06:00 [entrez]
PHST- 2011/05/06 06:00 [pubmed]
PHST- 2012/06/19 06:00 [medline]
AID - 10.1002/jat.1679 [doi]
PST - ppublish
SO  - J Appl Toxicol. 2012 Apr;32(4):282-92. doi: 10.1002/jat.1679. Epub 2011 May 4.