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J. Biol. Chem., Vol. 281, Issue 21, 14764-14775, May 26, 2006

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Auto-activation of the Apoptosis Protein Bax Increases Mitochondrial Membrane Permeability and Is Inhibited by Bcl-2^*

Chibing Tan, Paulina J. Dlugosz, Jun Peng, Zhi Zhang, Suzanne M. Lapolla, Scott M. Plafker^¶, David W. Andrews¹, and Jialing Lin²

From the Departments of Biochemistry and Molecular Biology and ^¶Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190 and the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

Interactions among Bcl-2 family proteins mediated by Bcl-2 homology (BH) regions transform apoptosis signals into actions. The interactions between BH3 region-only proteins and multi-BH region proteins such as Bax and Bcl-2 have been proposed to be the dominant interactions required for initiating apoptosis. Experimental evidence also suggests that both homo- and hetero-interactions are mediated primarily by the BH3 regions in all Bcl-2 family proteins and contribute to commitment to or inhibition of apoptosis. We found that a peptide containing the BH3 helix of Bax was not sufficient to activate recombinant Bax to permeabilize mitochondria. However, an extended peptide containing the BH3 helix and additional downstream sequences activated Bax to permeabilize mitochondria and liposomes. Bcl-2 inhibited the membrane-permeabilizing activity of peptide-activated Bax. This activity of Bcl-2 was inhibited by the extended but not the BH3-only peptide despite both peptides binding to Bcl-2 with similar affinity. Further, membrane-bound Bax activation intermediates directly activated soluble Bax further permeabilizing the membrane. Bcl-2 inhibited Bax auto-activation. We therefore propose that Bax auto-activation amplifies the initial death signal produced by BH3-only proteins and that Bcl-2 functions as an inhibitor of Bax auto-activation.

Received for publication, March 14, 2006

^* This work was supported by National Institutes of Health Grant GM062964 (to J. L.) and CIHR Grant FRN 12517 (to D. W. A.). 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 data.

¹ Holds the Canada Research Chair in Membrane Biogenesis.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 935, P.O. Box 26901, Oklahoma City, OK 73190. Tel.: 405-271-2227 (ext. 1216); Fax: 405-271-3092; E-mail: jialing-lin{at}ouhsc.edu.

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