BCL-2 family isoforms in apoptosis and cancer

Abstract

The BCl-2 family has long been identified for its role in apoptosis. Following the initial discovery of BCL-2 in the context of B-cell lymphoma in the 1980s, a number of homologous proteins have since been identified. The members of the Bcl-2 family are designated as such due to their BCL-2 homology (BH) domains and involvement in apoptosis regulation. The BH domains facilitate the family members’ interactions with each other and can indicate pro- or anti-apoptotic function. Traditionally, these proteins are categorised into one of the three subfamilies; anti-apoptotic, BH3-only (pro-apoptotic), and pore-forming or ‘executioner’ (pro-apoptotic) proteins. Each of the BH3-only or anti-apoptotic proteins has a distinct pattern of activation, localisation and response to cell death or survival stimuli. All of these can vary across cell or stress types, or developmental stage, and this can cause the delineation of the roles of BCL-2 family members. Added to this complexity is the presence of relatively uncharacterised isoforms of many of the BCL-2 family members. There is a gap in our knowledge regarding the function of BCL-2 family isoforms. BH domain status is not always predictive or indicative of protein function, and several other important sequences, which can contribute to apoptotic activity have been identified. While therapeutic strategies targeting the BCL-2 family are constantly under development, it is imperative that we understand the molecules, which we are attempting to target. This review, discusses our current knowledge of anti-apoptotic BCL-2 family isoforms. With significant improvements in the potential for splicing therapies, it is important that we begin to understand the distinctions of the BCL-2 family, not limited to just the mechanisms of apoptosis control, but in their roles outside of apoptosis.

BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

“…The permeability of the outer mitochondrial membrane is tightly controlled by members of BCL-2 family proteins via protein-protein interactions. The BCL-2 family of proteins consists of more than 20 different members classified based on the protein structure and key functions into three main subgroups, the anti-apoptotic proteins, the pro-apoptotic multi-domain effector proteins, and pro-apoptotic BCL-2 homology (BH)3 domain-only proteins [13]. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins can lead to disruption of the apoptotic process and the aberrant survival of cancer cells [14].…”

BCL-w: apoptotic and non-apoptotic role in health and disease

“…Anti-apoptotic members of this family, BCL-2 itself, B-cell lymphoma-extra-large (BCL-X L ), B-cell lymphoma-w (BCL-w), BCL-2-related protein A1/BCL-2related isolated from fetal liver-11 (A1/BFL-1) and myeloid cell leukemia-1 (MCL-1) 4,5 share four BCL-2homology (BH) domains (BH1-BH4), but A1/BFL-1 and certain isoforms of MCL-1 lack the BH4 domain ( Fig. 1a) 6 . The pro-apoptotic proteins such as BCL-2associated X protein (BAX) and BCL-2 antagonist/killer (BAK) possess BH1-BH3 motifs 4,5,7 .…”

Cell death in photodynamic therapy: From oxidative stress to anti-tumor immunity

“…The first has all the four BH domains (BH1, BH2, BH3 and BH4) and includes the BCL-2 itself, BCL-extra large (BCL-XL), myeloid cell leukemia-1 (MCL-1), BCL like 2 (BCLL2, best known as BCL-W), and BCL-family member A1 (BFL-1) proteins. The latter includes proteins with the BH1, BH2 and BH3 domains (e.g., BCL2 associated X (BAX), BCL2 antagonist killer 1 (BAK1) and BCL2 family apoptosis regulator (BOK)) and proteins that contain only the BH3 domain, commonly known as BH3-only proteins (e.g., BCL2 associated death promoter (BAD), BH3 interacting domain death agonist (BID), p53-upregulated modulator of apoptosis (PUMA), BCL2-interacting mediator of cell death (BIM) and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, best known as NOXA)) [75]. Intrinsic apoptosis may result from direct damage at the mitochondria or can be indirectly stimulated by signaling pathways activated due to damage inflicted to other cellular structures.…”