Nuclear distribution of claudin-2 increases cell proliferation in human lung adenocarcinoma cells.

Akira Ikari, Ryo Watanabe, Tomonari Sato, Saeko Taga, Shun Shimobaba, Masahiko Yamaguchi, Yasuhiro Yamazaki, Satoshi Endo, Toshiyuki Matsunaga, Junko Sugatani

Index: Biochim. Biophys. Acta 1843(9) , 2079-88, (2014)

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Abstract

Claudin-2 is expressed in human lung adenocarcinoma tissue and cell lines, although it is absent in normal lung tissue. However, the role of claudin-2 in cell proliferation and the regulatory mechanism of intracellular distribution remain undefined. Proliferation of human adenocarcinoma A549 cells was decreased by claudin-2 knockdown together with a decrease in the percentage of S phase cells. This knockdown decreased the expression levels of ZONAB and cell cycle regulators. Claudin-2 was distributed in the nucleus in human adenocarcinoma tissues and proliferating A549 cells. The nuclear distribution of ZONAB and percentage of S phase cells were higher in cells exogenously expressing claudin-2 with a nuclear localization signal than in cells expressing claudin-2 with a nuclear export signal. Nuclear claudin-2 formed a complex with ZO-1, ZONAB, and cyclin D1. Nuclear distribution of S208A mutant, a dephosphorylated form of claudin-2, was higher than that of wild type. We suggest that nuclear distribution of claudin-2 is up-regulated by dephosphorylation and claudin-2 serves to retain ZONAB and cyclin D1 in the nucleus, resulting in the enhancement of cell proliferation in lung adenocarcinoma cells. Copyright © 2014 Elsevier B.V. All rights reserved.