B-cell lymphoma 2 (Bcl-2) protein is an oncogene that normally acts as an apoptotic inhibitor and localizes to the mitochondrial membrane where it prevents the release of cytochrome c. The Bcl-2 protein family consists of over 20 proteins each containing at least one Bcl-2 homology (BH) domains and have either proapoptic or antiapoptotic activities. During induction of apoptosis the oligomerization of the Bcl-2 family proteins Bax and Bak forms a pore in the mitochondrial membrane triggering the release of cytochrome c. While it is still unclear, Bcl-2 is thought to directly bind and sequester BH-3 domain proapoptotic proteins such as BIM or BID. Upon release, BIM or BID are free to bind and activate Bax/Bak to induce cell death. Bcl-2 is often overexpressed in tumor cells where it can enhance cell survival despite the presence of apoptotic signals by sequestering the proapoptotic proteins. Additionally, some BH-3 domain proteins can function as sensitizers. They can disrupt the interaction of Bcl-2 and BIM or BID. This causes the release of proapoptotic signals that can then directly activate Bax/Bak. The interactions between Bcl-2 family proteins regulate the decision between cell death and survival. In cancer Bcl-2 family proteins are often mutated or misregulated making them promising targets for anticancer therapeutics.
The Letai group from the Dana-Farber Cancer Institute studied evolved resistance to Bcl-2 antagonists (1). In resistant cell lines they used a panel of antibodies against Bcl-2 family members, including the monoclonal Bcl-2 antibody, and found upregulation of Mcl-1and Bfl-1 protein levels conferred resistance through sequestration of Bim. In an attempt to target Bcl-2 overexpressing tumors Winkler et al. designed a delivery method for siRNAs against Bcl-2 (2). Using the Bcl-2 antibody they were able to show successful delivery and knockdown of Bcl-2 levels sufficient to induce apoptosis of tumor cells. In addition to the inhibition of apoptosis, Priault et al. showed Bcl-2 also contributes to cell survival by regulating pro-survival autophagy (3). Through immunoprecipitation experiments with the Bcl-2 antibody they identified an interaction with the essential autophagy protein Beclin-1. Additionally overexpression of Bcl-2 was able to stimulate autophagy. In an attempt to understand the role of Cyclophilin-D (CypD) overexpression in tumors the Gunter group performed immunoprecipitation experiments to identify interactions with apoptosis regulators (4). Using the Bcl-2 antibody they identified an interaction between CypD and Bcl-2 that prevented cytochrome c release and inhibited apoptosis. Disruption of the CypD/Bcl-2 interaction restored cell death suggesting a potential target in CypD overexpressing tumors. May et al. published research detailing the mechanism of the bacterial subtilase cytotoxin (SubAB) (5). They showed SubAB induces ER stress by cleaving BiP, an essential ER chaperone. The authors examined of Bcl-2 family proteins following SubAB exposure using a panel of antibodies including Bcl-2 antibody. They demonstrated SubAB induces apoptosis in a Bax/Bak-dependent manner.
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