Apoptosis is a form of cell death that is carried out by a pre-existing program within the cell. Apoptosis can be initiated by a number of external insults, such as growth factor withdrawal, DNA damage, or engagement of surface receptors. A critical step during apoptosis is the release of mitochondrial proteins that reside in the intermembrane space. Cytochrome c, for example, induces oligomerization of a 130 kD molecule called Apaf-1, leading to activation of cystein proteases (caspases). However, the molecular mechanisms involved in the premeabilization of the outer membrane of mitochondrira are poorly understood. Bcl-2 family proteins are known to regulate protein release from mitochondria; pro-apoptotic family members to permeabilize the membrane and anti-apoptotic members to counter the effect of pro-apoptotic ones. Further, it has been shown that a subset of pro-apoptotic Bcl-2 family members, called BH3-domain only members, work upstream of multi-domain pro-apoptotic family members to induce protein release. Using lipid vesicles and purified recombinant proteins, we hope to dissect molecular events that govern outer mitochondrial membrane permeabilization by Bcl-2 family proteins.

Selected publications:

1. Kuwana T*, Smith JJ*, Muzio M, Dixit V, Newmeyer DD, Kornbluth S. Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c. J. Biol. Chem. 273, 16589-16594 (1998).
   
   
2. Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD. Bid, Bax and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell 111, 331-342 (2002).
   
   
3. Kuwana T, Newmeyer DD. Bcl-2 family proteins and the role of mitochondria in apoptosis (review). Curr. Op. Cell Biol. 15, 691-699 (2003).
   
   
4. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010-1014 (2004).
   
   
5. Kuwana T*, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan B, Green DR, Newmeyer DD*. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirecty. Mol Cell 17, 525-535 (2005).
   

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