J. Cell Biol., Volume 143, Number 1, October 5, 1998 207-215

Regulated Targeting of BAX to Mitochondria

Ing Swie Goping,^* Atan Gross, Josée N. Lavoie,^* Mai Nguyen,^* Ronald Jemmerson,^§ Kevin Roth, Stanley J. Korsmeyer, and Gordon C. Shore^*

^* Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montreal, Quebec, Canada H3G 1Y6;  Division of Molecular Oncology, Department of Medicine and Department of Pathology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110; and ^§ Department of Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

The proapoptotic protein BAX contains a single predicted transmembrane domain at its COOH terminus. In unstimulated cells, BAX is located in the cytosol and in peripheral association with intracellular membranes including mitochondria, but inserts into mitochondrial membranes after a death signal. This failure to insert into mitochondrial membrane in the absence of a death signal correlates with repression of the transmembrane signal-anchor function of BAX by the NH₂-terminal domain. Targeting can be instated by deleting the domain or by replacing the BAX transmembrane segment with that of BCL-2. In stimulated cells, the contribution of the NH₂ terminus of BAX correlates with further exposure of this domain after membrane insertion of the protein. The peptidyl caspase inhibitor zVAD-fmk partly blocks the stimulated mitochondrial membrane insertion of BAX in vivo, which is consistent with the ability of apoptotic cell extracts to support mitochondrial targeting of BAX in vitro, dependent on activation of caspase(s). Taken together, our results suggest that regulated targeting of BAX to mitochondria in response to a death signal is mediated by discrete domains within the BAX polypeptide. The contribution of one or more caspases may reflect an initiation and/or amplification of this regulated targeting.

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• Pyrzynska, B., Serrano, M., Martinez-A., C., Kaminska, B. (2002). Tumor Suppressor p53 Mediates Apoptotic Cell Death Triggered by Cyclosporin A. J. Biol. Chem. 277: 14102-14108 [Abstract] [Full Text]  
• Breckenridge, D. G., Nguyen, M., Kuppig, S., Reth, M., Shore, G. C. (2002). The procaspase-8 isoform, procaspase-8L, recruited to the BAP31 complex at the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 99: 4331-4336 [Abstract] [Full Text]  
• Cartron, P.-F., Oliver, L., Martin, S., Moreau, C., LeCabellec, M.-T., Jezequel, P., Meflah, K., Vallette, F. M. (2002). The expression of a new variant of the pro-apoptotic molecule Bax, Bax{psi}, is correlated with an increased survival of glioblastoma multiforme patients. Hum Mol Genet 11: 675-687 [Abstract] [Full Text]  
• Maianski, N. A., Mul, F. P. J., van Buul, J. D., Roos, D., Kuijpers, T. W. (2002). Granulocyte colony-stimulating factor inhibits the mitochondria-dependent activation of caspase-3 in neutrophils. Blood 99: 672-679 [Abstract] [Full Text]  
• Perfettini, J.-L., Reed, J. C., Israel, N., Martinou, J.-C., Dautry-Varsat, A., Ojcius, D. M. (2002). Role of Bcl-2 Family Members in Caspase-Independent Apoptosis during Chlamydia Infection. Infect. Immun. 70: 55-61 [Abstract] [Full Text]  
• Wang, G.-Q., Wieckowski, E., Goldstein, L. A., Gastman, B. R., Rabinovitz, A., Gambotto, A., Li, S., Fang, B., Yin, X.-M., Rabinowich, H. (2001). Resistance to Granzyme B-mediated Cytochrome c Release in Bak-deficient Cells. JEM 194: 1325-1338 [Abstract] [Full Text]  
• Yao, P. M., Tabas, I. (2001). Free Cholesterol Loading of Macrophages Is Associated with Widespread Mitochondrial Dysfunction and Activation of the Mitochondrial Apoptosis Pathway. J. Biol. Chem. 276: 42468-42476 [Abstract] [Full Text]  
• Luetjens, C. M., Kogel, D., Reimertz, C., Du{beta}mann, H., Renz, A., Schulze-Osthoff, K., Nieminen, A.-L., Poppe, M., Prehn, J. H. M. (2001). Multiple Kinetics of Mitochondrial Cytochrome c Release in Drug-Induced Apoptosis. Mol. Pharmacol. 60: 1008-1019 [Abstract] [Full Text]  
• Sundararajan, R., White, E. (2001). E1B 19K Blocks Bax Oligomerization and Tumor Necrosis Factor Alpha-Mediated Apoptosis. J. Virol. 75: 7506-7516 [Abstract] [Full Text]  

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