Every day, the average adult loses approximately 60 billion cells due to apoptosis.1
Although apoptosis facilitates the cellular turnover that is required to maintain homeostasis and plays important roles in development, misregulated apoptotic processes can contribute to disease. Indeed, a disruption of the balance between cell death and proliferation is a feature of many cancers. Apoptosis is controlled by a tightly regulated process that is conserved across metazoans and involves proteins related to the B-cell lymphoma 2 (BCL-2) family. Characterization of the BCL2
oncogene and the BCL-2 protein family led to the current appreciation of the significant role that apoptosis plays in many types of malignancies. This understanding has motivated the current advancements in cancer therapeutics that target different members of apoptotic regulatory networks.The BCL2 Gene Family
The gene encoding BCL-2 was cloned from the breakpoint of the common chromosomal translocation that is observed in patients with follicular lymphoma (FL) t(14;18).2
The suspected oncogenic properties of this gene were confirmed when BCL-2 overexpression was shown to confer a survival advantage to cells, somehow preventing them from undergoing programmed cell death.3
The ability of BCL-2 to block cell death signaling was a novel oncogenic feature; at the time, all the known oncogenes caused cancer by interfering with cell proliferation mechanisms. The BCL-2 family members have since been implicated in both proapoptotic and antiapoptotic roles and are established master-regulators of apoptosis. Discovery and Characterization
Since the initial characterization of BCL-2 more than 3 decades ago, at least 30 other BCL-2 family members have been identified. The defining feature of the BCL-2 family members is the presence of ≥1 BCL-2 homology (BH) domains. The BCL-2 family members fall into 3 subcategories, based on function and structural features: (1) the prosurvival members, (2) the proapoptotic members, and (3) the BH3–only members (Figure
Figure. The BCL-2 Protein Family4
Known helical and transmembrane regions are indicated, as well as BH domains 1-4.
Figure reprinted with open access from Adams JM, Cory S. Cell Death Differ. 2018;25(1):27-36.
In addition to BCL-2, the human prosurvival family members include BCL-XL
, BCL-W, MCL-1, and BFL1.5
These proteins each harbor 4 BCL-2 homology domains (BH1-BH4). Together, these homology domains form the tertiary structure that interacts directly with the proapoptotic family members. BCL-2 and the other prosurvival proteins are localized on the mitochondrial outer membrane and promote cell survival by binding to and sequestering the proapoptotic family members.
The proapoptotic members also contain multiple BH domains and have a structure that is similar to that of the prosurvival members until they are activated, upon which they undergo conformational change.6
The proapoptotic family members, also referred to as pore-formers for their role in mitochondrial outer membrane permeabilization (MOMP), include BAX, BAK, and BOK. BAX was discovered by an immunoprecipitation experiment searching for proteins that interact with BCL-2 and, upon characterization, was the first indication that some BCL-2 family members perform a proapoptotic role.7
Two years later, BAK was discovered via a polymerase chain reaction screen searching for genes encoding BH-domain–containing proteins.8
BAX and BAK interact with different members of the prosurvival group to contribute to apoptosis regulation. Cells missing either protein are largely unaffected, but the disruption of both proteins interferes with apoptosis, as mice with both genes knocked out maintain cells that would otherwise undergo apoptosis during development.9
The function of BOK remains unclear.10
BH3-only family members are proapoptotic proteins that include BIM, PUMA, BAD, BMF, BID, NOXA, HRK, and BIK. These members are more distantly related to each other; the similar feature they share is the BH3 domain.11
This subcategory is further divided into activator and sensitizer proteins; activators can directly bind to and activate BAX/BAK, whereas sensitizers bind to and inhibit antiapoptotic proteins. These proteins are natively unfolded and adopt structures upon interaction with binding partners, except BID and probably BIK.12BCL-2 Function