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J. Biol. Chem., Vol. 281, Issue 43, 32469-32484, October 27, 2006

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Calreticulin Represses E-cadherin Gene Expression in Madin-Darby Canine Kidney Cells via Slug^*

Yasushi Hayashida¹, Yoshishige Urata, Eiji Muroi, Takaaki Kono, Yasuyoshi Miyata, Koichiro Nomata, Hiroshi Kanetake, Takahito Kondo, and Yoshito Ihara^¶12

From the Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, and the ^¶Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-1102, Japan

Calreticulin (CRT) is a multifunctional Ca²⁺-binding molecular chaperone in the endoplasmic reticulum. In mammals, the expression level of CRT differs markedly in a variety of organs and tissues, suggesting that CRT plays a specific role in each cell type. In the present study, we focused on CRT functions in the kidney, where overall expression of CRT is quite low, and established CRT-overexpressing kidney epithelial cell-derived Madin-Darby canine kidney cells by gene transfection. We demonstrated that, in CRT-overexpressing cells, the morphology was apparently changed, and the original polarized epithelial cell phenotype was destroyed. Furthermore, CRT-overexpressing cells showed enhanced migration through Matrigel®-coated Boyden chamber wells, compared with controls. E-cadherin expression was significantly suppressed at the protein and transcriptional levels in CRT-overexpressing cells compared with controls. On the other hand, the expression of mesenchymal protein markers, such as N-cadherin and fibronectin, was up-regulated. We also found that the expression of Slug, a repressor of the E-cadherin promoter, was up-regulated by overexpression of CRT through altered Ca²⁺ homeostasis, and this led to enhanced binding of Slug to the E-box element in the E-cadherin promoter. Thus, we conclude that CRT regulates the epithelial-mesenchymal transition-like change of cellular phenotype by modulating the Slug/E-cadherin pathway through altered Ca²⁺ homeostasis in cells, suggesting a novel function of CRT in cell-cell interaction of epithelial cells.

Received for publication, July 31, 2006

^* This work was supported in part by grants-in-aid from the Ministry of Education, Science, Sports, Culture, and Technology of Japan, and fellowship from The Tsukushi Foundation (YH). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Yoshito Ihara, Tel.: +81 95-849-7099; Fax: +81 95-849-7100; E-mail: y-ihara{at}net.nagasaki-u.ac.jp.

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