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J. Biol. Chem., Vol. 281, Issue 5, 2750-2756, February 3, 2006

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Quantitative Proteomic Analysis of Myc-induced Apoptosis

A DIRECT ROLE FOR Myc INDUCTION OF THE MITOCHONDRIAL CHLORIDE ION CHANNEL, mtCLIC/CLIC4^*

Yuzuru Shiio^¶1, Kwang S. Suh^||, Hookeun Lee^**, Stuart H. Yuspa^||, Robert N. Eisenman², and Ruedi Aebersold^**

From the Institute for Systems Biology, Seattle, Washington 98103-8904, the Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, the ^¶Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, the ^||Laboratory of Cellular Carcinogenesis and Tumor Promotion, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, and the ^**Institute for Molecular Systems Biology, Eidgenössische Technische Hochschule-Zurich and Faculty of Natural Sciences, University of Zurich, CH-8093, Switzerland

Myc is a key regulatory protein in higher eukaryotes controlling important cellular functions such as proliferation, differentiation, and apoptosis. Myc is profoundly involved in the genesis of many human and animal cancers, and the abrogation of Myc-induced apoptosis is a critical event in cancer progression. Because the mechanisms that mediate Myc-induced apoptosis are largely unknown, we analyzed protein expression during Myc-induced apoptosis using an isotope-coded affinity tag quantitative proteomics approach and identified that a proapoptotic mitochondrial chloride ion channel, mtCLIC/CLIC4, is induced by Myc. Myc binds to the mtCLIC gene promoter and activates its transcription. Suppression of mtCLIC expression by RNA interference inhibited Myc-induced apoptosis in response to different stress conditions and abolished the cooperative induction of apoptosis by Myc and Bax. We also found that Myc reduces the expression of Bcl-2 and Bcl-xL and that the apoptosis-inducing stimuli up-regulate Bax expression. These results suggest that up-regulation of mtCLIC, together with a reduction in Bcl-2 and Bcl-xL, sensitizes Myc-expressing cells to the proapoptotic action of Bax.

Received for publication, August 24, 2005 , and in revised form, November 22, 2005.

^* This work was supported in part by grants from the National Institutes of Health (to R. N. E. and R. A.), the Federal Fund from the NHBLI, National Institutes of Health under Contract N01-HV-28179, the Interdisciplinary Research Training Fellowship from the Fred Hutchinson Cancer Research Center (to Y. S.), and a gift from Merck and Co. to the Institute for Systems Biology. 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.

² A Research Professor of the American Cancer Society.

¹ To whom correspondence should be addressed: Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-562-9089; Fax: 210-562-9014; E-mail: shiio{at}uthscsa.edu.

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