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.

Fig. 1. Schematic diagram of BCL-2.

Comprised of three exons, with the first two exons encoding the four BH domains and exon 3 encoding the transmembrane domain, with BCL-2β lacking the transmembrane domain

Fig. 2. Primary protein structures of BCL-2α and BCL-2β.

This figure is based on experiments on BCL-2 and the highly homologous BCL-X_L. It illustrates the similarities between the isoforms. BH1, BH2, and BH3 are required for heterodimerisation with BCL-2 family members^,,. Channels are formed by α-helices 5 and 6. Phosphorylation by MAPK8 (mitogen-activated kinase 8) at specific residues between BH4 and BH3 can modify binding to Beclin-1. Caspase-3 cleavage at amino acids 34–35 can abrogate protein function. The two proteins are identical up to amino acid 196, where they start to differ, with BCL-2β lacking a transmembrane domain and having a specific C-terminal 9-amino acid sequence. This figure was adapted from Belka and Budach (2002)