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Am J Physiol Gastrointest Liver Physiol 294: G336-G343, 2008. First published November 21, 2007; doi:10.1152/ajpgi.00328.2007
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LIVER AND BILIARY TRACT

Transcriptional activation of the human claudin-18 gene promoter through two AP-1 motifs in PMA-stimulated MKN45 gastric cancer cells

Koichi Yano, Takashi Imaeda, and Tomoaki Niimi

Department of Bioengineering Sciences, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya, Japan

Submitted 20 July 2007 ; accepted in final form 14 November 2007

Claudin-18 (CLDN18), a member of the claudin family of proteins that are structural components of tight junctions, has two alternatively spliced variants, claudin-18a1 and claudin-18a2, which are highly expressed in lung and stomach, respectively. Downregulation of claudin-18a2 is associated with gastric cancers of an intestinal phenotype; however, the mechanisms regulating its expression have not been defined. Here, we found that phorbol 12-myristate 13-acetate (PMA) treatment of MKN45 human gastric cancer cell line increased claudin-18a2 expression. In addition, this study aimed to characterize the human CLDN18a2 promoter. Using reporter gene assays and deletion analysis, we mapped the critical promoter region of the PMA-stimulated claudin-18a2 expression to the –923/–286 region. Electrophoretic mobility shift assays and mutational analyses revealed that two activator protein (AP)-1 binding sites played an important role in the expression of claudin-18a2 in PMA-stimulated MKN45 cells. Protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) inhibitors suppressed the upregulation of claudin-18a2. These results indicate that the PKC/MAPK/AP-1 dependent pathway regulates claudin-18a2 expression in gastric cells.

activator protein-1; phorbol 12-myristate 13-acetate; stomach; tight junction


Address for reprint requests and other correspondence: T. Niimi, Dept. of Bioengineering Sciences, Graduate School of Bioagricultural Sciences, Nagoya Univ., Chikusa, Nagoya 464-8601, Japan (e-mail: tniimi{at}agr.nagoya-u.ac.jp)






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