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Molecular and Cellular Biology, June 2002, p. 3610-3620, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3610-3620.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

mtCLIC/CLIC4, an Organellular Chloride Channel Protein, Is Increased by DNA Damage and Participates in the Apoptotic Response to p53

Ester Fernández-Salas,1,{dagger} Kwang S. Suh,1 Vladislav V. Speransky,2 Wendy L. Bowers,1 Joshua M. Levy,1 Tracey Adams,1 Kamal R. Pathak,1 Lindsay E. Edwards,1 Daniel D. Hayes,1 Christina Cheng,1 Alasdair C. Steven,2 Wendy C. Weinberg,3 and Stuart H. Yuspa1*

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute,1 Laboratory of Structural Biology Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health,2 Laboratory of Immunobiology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 208923

Received 4 October 2001/ Returned for modification 15 November 2001/ Accepted 22 February 2002

mtCLIC/CLIC4 (referred to here as mtCLIC) is a p53- and tumor necrosis factor alpha-regulated cytoplasmic and mitochondrial protein that belongs to the CLIC family of intracellular chloride channels. mtCLIC associates with the inner mitochondrial membrane. Dual regulation of mtCLIC by two stress response pathways suggested that this chloride channel protein might contribute to the cellular response to cytotoxic stimuli. DNA damage or overexpression of p53 upregulates mtCLIC and induces apoptosis. Overexpression of mtCLIC by transient transfection reduces mitochondrial membrane potential, releases cytochrome c into the cytoplasm, activates caspases, and induces apoptosis. mtCLIC is additive with Bax in inducing apoptosis without a physical association of the two proteins. Antisense mtCLIC prevents the increase in mtCLIC levels and reduces apoptosis induced by p53 but not apoptosis induced by Bax, suggesting that the two proapoptotic proteins function through independent pathways. Our studies indicate that mtCLIC, like Bax, Noxa, p53AIP1, and PUMA, participates in a stress-induced death pathway converging on mitochondria and should be considered a target for cancer therapy through genetic or pharmacologic approaches.

* Corresponding author. Mailing address: Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-2162. Fax: (301) 496-8709. E-mail: yuspas{at}dc37a.nci.nih.gov.

{dagger} Present address: Neurotoxin Research Program, Department of Biological Sciences, Allergan Pharmaceuticals, Irvine, CA 92612.

Molecular and Cellular Biology, June 2002, p. 3610-3620, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3610-3620.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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