title: Nuclear distribution of claudin-2 increases cell proliferation in human lung adenocarcinoma cells.
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.
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan; School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address: ikari@gifu-pu.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Ikari
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Sato
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Saeko
authors.initials: S
authors.lastname: Taga
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Shimobaba
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.affiliation: Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sugatani
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D057167:Claudins / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D050505:Mutant Proteins / Q000378:metabolism; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D013997:Time Factors; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C491875:CLDN2 protein, human; D018797:Cell Cycle Proteins; D057167:Claudins; D006360:Heat-Shock Proteins; D050505:Mutant Proteins; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; C569042:TJP1 protein, human; C094867:YBX3 protein, human; D062826:Zonula Occludens-1 Protein; D019938:Cyclin D1; D005576:Colforsin
keywords: Adenocarcinoma; Cell proliferation; Claudin-2; Nuclear distribution