The discovery of the bcl-2 gene was of pivotal importance for apoptosis research. This gene was identified by virtue of its localization near the t(14;18) chromosomal breakpoint in many human lymphomas, which causes increased transcription of the gene. Subsequently, the Bcl-2 protein was shown to suppress apoptosis when overexpressed in a lymphocyte cell line. Since that time, 26 bcl-2-related genes have been cloned and their function during apoptosis partially analyzed. Some of these proteins are antiapoptotic and some are proapoptotic. All of these proteins contain at least one of four conserved Bcl-2 homology (BH) motifs. Every antiapoptotic member except E1B-19K of adenovirus contains both BH1 and BH2. These include bcl-2, bcl-xL, bcl-w, mcl-1, A1, NR-13, BHRF1, LMW5-HL, ORF16, KS-bcl-2, boo, and ced-9. In addition, there are two subclasses of proapoptotic Bcl-2 family members. The Bax subfamily consists of bax, bak, bok, and Diva; the BH3 subfamily includes bik, blk, hrk, BNIP3, Bim, bad, bid, and egl-1, bcl-xs, and bod. The expression of these genes is described in Table 2.
The activity of many of these Bcl-2 family members is regulated by heterodimerization, and in some cases by phosphorylation. These proteins also vary in their tissue and/or differentiation specific expression, and in their affinity for different partners. Anti-apoptotic family members and those of the pro-apoptotic Bax subfamily can act in the absence of a partner, but members of the BH3 subfamily apparently must heterodimerize with antiapoptotic family members to exert their effect. Therefore, both the balance of pro- vs antiapoptotic proteins in a cell and their ability to bind to one another may regulate the ability of the cell to undergo programmed cell death.
Potential ways in which Bcl-2 and Bcl-xL may protect cells from apoptosis include regulating cellular redox potential and/or membrane permeability, preventing cytochrome c efflux from mitochondria, regulating ion homeostasis, anchoring proapoptotic proteins to mitochondrial membranes, or inhibiting association of Apaf-1 with procaspase-9. Structural similarity of the other antiapoptotic family members with Bcl-2 and Bcl-xL suggest they may act in a similar manner. Many of the proapoptotic Bcl-2 family members act by binding to and thereby abrogating the effects of the antiapoptotic proteins. However, the proapoptotic protein Diva functions by binding to Apaf-1 and preventing association of this protein with Bcl-xL. Members of the Bax subfamily also seem to be able to induce apoptosis by damaging organelles by insertion into membranes. These proteins are able to directly induce release of cytochrome c from mitochondria, with subsequent activation of downstream caspases. The proapoptotic protein Bid is normally cytosolic, and is cleaved by caspase-8 after engagement of the Fas receptor or TNFR1 in certain cells. Truncated Bid then translocates to the mitochondria, induces clustering of these organelles, and causes release of cytochrome c. It is inevitable that as each of these proteins is studied in depth, unique modes of interaction with the apoptotic machinery will be identified.
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