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J. Biol. Chem., Vol. 280, Issue 19, 19051-19061, May 13, 2005

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Bax-dependent Regulation of Bak by Voltage-dependent Anion Channel 2^*

Dhyan Chandra¶, Grace Choy||, Peter T. Daniel**, and Dean G. Tang

From the Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957 and the ^**Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charite, Campus Berlin-Buch, Humboldt University, 13125 Berlin, Germany

Many studies have demonstrated a critical role of Bax in mediating apoptosis, but the role of Bak in regulating cancer cell apoptotic sensitivities in the presence or absence of Bax remains incompletely understood. Using isogenic cells with defined genetic deficiencies, here we show that in response to intrinsic, extrinsic, and endoplasmic reticulum stress stimuli, HCT116 cells show clear-cut apoptotic sensitivities in the order of Bax⁺/Bak⁺ > Bax⁺/Bak^– » Bax^–/Bak⁺ » Bax^–/Bak^–. Small interference RNA-mediated knockdown of Bak in Bax-deficient cells renders HCT116 cells completely resistant to apoptosis induction. Surprisingly, however, Bak knockdown in Bax-expressing cells only slightly affects the apoptotic sensitivities. Bak, like Bax, undergoes the N terminus exposure upon apoptotic stimulation in both Bax-expressing and Bax-deficient cells. Gel filtration, chemical cross-linking, and co-immunoprecipitation experiments reveal that different from Bax, which normally exists as monomers in unstimulated cells and is oligomerized by apoptotic stimulation, most Bak in unstimulated HCT116 cells exists in two distinct protein complexes, one of which contains voltage-dependent anion channel (VDAC) 2. During apoptosis, Bak and Bax form both homo- and hetero-oligomeric complexes that still retain some VDAC-2. However, the oligomeric VDAC-2 complexes are diminished, and Bak does not interact with VDAC-2 in Bax-deficient HCT116 cells. These results highlight VDAC-2 as a critical inhibitor of Bak-mediated apoptotic responses.

Received for publication, February 7, 2005 , and in revised form, March 7, 2005.

^* This work was supported in part by National Institutes of Health Grants CA 90297 and AG023374, American Cancer Society Grant RSG MGO-105961, Department of Defense Grant DAMD17-03-1-0137, and National Institutes of Health, NIEHS Grant ES07784. 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–S3.

These authors contributed equally to this work.

^¶ Supported by Department of Defense Postdoctoral Traineeship Award DAMD17-02-0083.

^|| Supported by Department of Defense Postdoctoral Traineeship Award PC040684.

To whom correspondence should be addressed: Dept. of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park Research Division, Park Rd. 1C, Smithville, TX 78957. Tel.: 512-237-9575; Fax: 512-237-2475; E-mail: dtang{at}sprd1.mdacc.tmc.edu.

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