Bcl-2
Introduction
The average human adult makes around 60 billion cells a day, and concurrently eradicates approximately the same number. The Bcl-2 family plays a major role in regulation of apoptosis and so is crucial in controlling this eradication process in order to constrain and maintain cell numbers. Bcl-2 was actually the first anti-death gene discovered. The family consists of pro- and anti-apoptotic proteins that do this through regulation of the permeabilization of the outer mitochondrial membrane. A more permeable mitochondrial membrane allows cytochrome c and other apoptotic factors to enter the cytosol, causing the caspase cascade that commits the cell to death. Therefore, Bcl-2 affects the intrinsic mechanism of apoptosis. As a result, these proteins are important in tissue homeostasis, embryonic development and immunity.
All of the antiapoptotic members of the human Bcl-2 family consist of BH1-4 domains. Mammalian proapoptotic proteins lack the BH4 domain. Both members have the same basic tertiary protein structure, with a bundle of six or seven amphipathic alpha-helices encasing a core pair of hydrophobic alpha-helices. Bcl-2 is located at the OMM because it contains a transmembrane region. As can be seen from the diagram, the anti-apoptotic Bcl-2 protein of interest directly binds to Bax/Bak to prevent the complex from creating pores in the outer mitochondrial membrane through formation of homo-oligomers. The protein can also be bound by the inducers BH3-only protein, which leads to the release of Bax/Bak from Bcl-2, thereby indirectly activating apoptosis.
Bcl-2’s importance in cell death gives it a broad relevance in oncology. In fact, the discovery of the founding member of the gene family, Bcl-2, was due to its involvement in the t(14;18) chromosomal translocation seen in non-Hodgkin’s lymphoma. Defects in expression of the family’s pro-apoptotic members can lead to cancer, whereby the tumour suppressor function is lost. Therefore, targeting its mRNAs or proteins may be leading the way for a new anti-cancer drug.
References:
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