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.
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.
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