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J. Biol. Chem., Vol. 283, Issue 14, 9157-9167, April 4, 2008

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Novel Role of Antioxidant-1 (Atox1) as a Copper-dependent Transcription Factor Involved in Cell Proliferation^*

Shinichi Itoh¹, Ha Won Kim¹, Osamu Nakagawa^¶, Kiyoshi Ozumi, Susan M. Lessner^||, Hiroki Aoki^**, Kamran Akram, Ronald D. McKinney, Masuko Ushio-Fukai, and Tohru Fukai²

From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, the Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois 60612, the ^¶Division of Cardiology, Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, the ^||Department of Cell and Developmental Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29208, the ^**Department of Molecular Cardiovascular Biology, Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505, Japan, and the Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois 60612

Copper plays a fundamental role in regulating cell growth. Many types of human cancer tissues have higher copper levels than normal tissues. Copper can also induce gene expression. However, transcription factors that mediate copper-induced cell proliferation have not been identified in mammals. Here we show that antioxidant-1 (Atox1), previously appreciated as a copper chaperone, represents a novel copper-dependent transcription factor that mediates copper-induced cell proliferation. Stimulation of mouse embryonic fibroblasts (MEFs) with copper markedly increased cell proliferation, cyclin D1 expression, and entry into S phase, which were completely abolished in Atox1^-/- MEFs. Promoter analysis and EMSA revealed that copper stimulates the Atox1 binding to a previously undescribed cis element in the cyclin D1 promoter. The ChIP assay confirms that copper stimulates Atox1 binding to the DNA in vivo. Transfection of Atox1 fused to the DNA-binding domain of Gal4 demonstrated a copper-dependent transactivation in various cell types, including endothelial and cancer cells. Furthermore, Atox1 translocated to the nucleus in response to copper through its highly conserved C-terminal KKTGK motif and N-terminal copper-binding sites. Finally, the functional role of nuclear Atox1 is demonstrated by the observation that re-expression of nuclear-targeted Atox1 in Atox1^-/- MEFs rescued the defective copper-induced cell proliferation. Thus, Atox1 functions as a novel transcription factor that, when activated by copper, undergoes nuclear translocation, DNA binding, and transactivation, thereby contributing to cell proliferation.

Received for publication, November 19, 2007 , and in revised form, January 29, 2008.

^* This work was supported by National Institutes of Health Grants R01 HL70187 (to T. F.), P01 HL58000 (to T. F.), and American Heart Association Grant-In-aid 0455242B (to T. F.), R01 HL 077524 (to M. U.-F.), and American Heart Association Grant-in-aid 0555308B and 0755805Z (to M.U.-F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S7 and Table S1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: 835 S. Wolcott, M/C868, E403 MSB, Chicago, IL 60612. Tel.: 312-996-7631; E-mail: tfukai{at}uic.edu.

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