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J. Biol. Chem., Vol. 279, Issue 6, 4632-4641, February 6, 2004

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The Organellular Chloride Channel Protein CLIC4/mtCLIC Translocates to the Nucleus in Response to Cellular Stress and Accelerates Apoptosis^*

Kwang S. Suh, Michihiro Mutoh, Kunio Nagashima, Ester Fernandez-Salas¶, Lindsay E. Edwards||, Daniel D. Hayes**, John M. Crutchley, Keith G. Marin, Rebecca A. Dumont, Joshua M. Levy, Christina Cheng, Susan Garfield, and Stuart H. Yuspa

From the Laboratory of Cellular Carcinogenesis and Tumor Promotion and Confocal Microscopy Core Facility, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, NCI, National Institutes of Health (NIH), Bethesda, Maryland 20892 and the Electron Microscope Facility, Image Analysis Laboratory, NCI-Frederick, NIH, Science Applications International Corp., Inc., Frederick, Maryland 21702

CLIC4/mtCLIC, a chloride intracellular channel protein, localizes to the mitochondria and cytoplasm of keratinocytes and participates in the apoptotic response to stress. We now show that multiple stress inducers cause the translocation of cytoplasmic CLIC4 to the nucleus. Immunogold electron microscopy and confocal analyses indicate that nuclear CLIC4 is detected prior to the apoptotic phenotype. CLIC4 associates with the Ran, NTF2, and Importin- nuclear import complexes in immunoprecipitates of lysates from cells treated with apoptotic/stress-inducing agents. Deletion or mutation of the nuclear localization signal in the C terminus of CLIC4 eliminates nuclear translocation, whereas N terminus deletion enhances nuclear localization. Targeting CLIC4 to the nucleus via adenoviral transduction accelerates apoptosis when compared with cytoplasmic CLIC4, and only nuclear-targeted CLIC4 causes apoptosis in Apaf null mouse fibroblasts or in Bcl-2-overexpressing keratinocytes. These results indicate that CLIC4 nuclear translocation is an integral part of the cellular response to stress and may contribute to the initiation of nuclear alterations that are associated with apoptosis.

Received for publication, October 23, 2003 , and in revised form, November 10, 2003.

^* 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.

^¶ Present address: Allergan Pharmaceuticals, Irvine, CA 92612.

^|| Present address: Influenza Branch, Centers for Disease Control, Atlanta, GA 30333.

^** Present address: State University of New York, Upstate Medical University, Syracuse, NY 13210.

To whom correspondence should be addressed. Tel.: 301-496-2162; Fax: 301-496-8709; E-mail: yuspas{at}dc37a.nci.nih.gov.

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