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研究発表を行った学会；
・第37回日本分子生物学会年会
　２０１４年１１月２５日〜２７日（横浜）
タイトル；Aberrant splicing of zinc transporter ZIP2 causes mucus hypersecretory phenotype in cystic fibrosis airway epithelial cells.
発表者；亀井　竣輔　氏
　　　（熊本大学　大学院薬学教育部　遺伝子機能応用学分野）
Abstract；
Zinc ion (Zn2+) is an essential dietary metal ion that has pleiotropic effects in airway epithelial cells. Although patients with cystic fibrosis (CF), a common human hereditary pulmonary disease characterized by mucus hypersecretory phenotype, have a defect in regulation of intracellular Zn2+ level, the cellular and molecular mechanisms of Zn deficiency are largely unknown.
Our preliminary microarray analysis focusing on zinc-related genes suggest that Zrt-Irt-like Protein 2 (ZIP2), a member of the SLC39A family that is expressed at plasma membrane and transports zinc ion into the cells, seems to be selectively dysregulated in airway specific bENaC-transgenic mice, a model exhibits CF-like pulmonary phenotypes. To better understand the mechanism responsible for ZIP2 dysregulation and the relationship between ZIP2 dysregulation and pulmonary phenotype of CF, we first compared the expression levels and patterns of ZIP2 genes in human non-CF bronchial epithelial 16HBE14o- cells, primary airway epithelial cells (DHBE-CF) and cell line (CFBE41o-) derived from CF patients, and b/gENaC-overexpressing CF-like airway epithelial cell line (b/gENaC-16HBE14o-). Importantly, increased expression of the aberrant splicing isoform of ZIP2 (DC-ZIP2) in CF-related cells, and inverse correlation of expression between normal ZIP2 and DC-ZIP2 genes was confirmed. Moreover, in addition to decreased ZIP2 protein expression in CF-related cells, predominant existence of the cellular subset with lower zinc concentration was observed. Notably, reduction of intracellular zinc concentration with a zinc chelator TPEN up-regulated MUC5AC gene expression in non-CF cells, suggests an important role of zinc concentration in the regulation of mucus hypersecretory phenotype. Thus, our finding demonstrates that aberrant splicing of ZIP2 is a critical determinant factor that causes mucus hypersecretory phenotype in CF and CF-like airway epithelial cells.