AP2α is essential for MUC8 gene expression in human airway epithelial cells |
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Authors: | Uk Yeol Moon Chang‐Hoon Kim Jae Young Choi Yoon‐Ju Kim Yeon Ho Choi Ho‐Geun Yoon Hyeyoung Kim Joo‐Heon Yoon |
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Affiliation: | 1. The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, South Korea;2. Research Center for Natural Human Defense System, Yonsei University College of Medicine, Seoul, South Korea;3. Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea;4. BK 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea;5. Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea;6. Department of Food and Nutrition, Yonsei University College of Human Ecology, Seoul, South Korea |
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Abstract: | Mucins are high molecular weight proteins that make up the major components of mucus. Hypersecretion of mucus is a feature of several chronic inflammatory airway diseases. MUC8 is an important component of airway mucus, and its gene expression is upregulated in nasal polyp epithelium. Little is known about the molecular mechanisms of MUC8 gene expression. We first observed overexpression of activator protein‐2alpha (AP2α) in human nasal polyp epithelium. We hypothesized that AP2α overexpression in nasal polyp epithelium correlates closely with MUC8 gene expression. We demonstrated that phorbol 12‐myristate 13‐acetate (PMA) treatment of the airway epithelial cell line NCI‐H292 increases MUC8 gene and AP2α expression. In this study, we sought to determine which signal pathway is involved in PMA‐induced MUC8 gene expression. The results show that the protein kinase C and mitogen‐activating protein/ERK kinase (MAPK) pathways modulate MUC8 gene expression. PD98059 or ERK1/2 siRNA and RO‐31‐8220 or PKC siRNA significantly suppress AP2α as well as MUC8 gene expression in PMA‐treated cells. To verify the role of AP2α, we specifically knocked down AP2α expression with siRNA. A significant AP2α knock‐down inhibited PMA‐induced MUC8 gene expression. While dominant negative AP2α decreased PMA‐induced MUC8 gene expression, overexpressing wildtype AP2α increased MUC8 gene expression. Furthermore, using lentiviral vectors for RNA interference in human nasal polyp epithelial cells, we confirmed an essential role for AP2α in MUC8 gene expression. From these results, we concluded that PMA induces MUC8 gene expression through a mechanism involving PKC, ERK1/2, and AP2α activation in human airway epithelial cells. J. Cell. Biochem. 110: 1386–1398, 2010. © 2010 Wiley‐Liss, Inc. |
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Keywords: | MUC8 AP2α PMA ERK1/2 |
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