BCL-2 gene family and the regulation of programmed cell death.

The BCL-2 gene was identified at the chromosomal breakpoint of t(14; 18)-bearing human follicular B cell lymphomas. BCL-2 proved to block programmed cell death rather than promote proliferation. Transgenic mice that overexpress Bcl-2 in the B cell lineage demonstrate extended cell survival and progress to high-grade lymphomas. Thus, BCL-2 initiated a new category of oncogenes, regulators of cell death. Bcl-2-deficient mice demonstrate fulminant apoptosis of lymphocytes, profound renal cell death and loss of melanocytes. BCL-2 protein duels with its counteracting twin, a partner known as BAX. When BAX is in excess, cells execute a death command; but, when BCL-2 dominates, the program is inhibited and cells survive. Bax-deficient mice display cellular hyperplasia, confirming its role as a proapoptotic molecule. An expanded family of BCL-2-related proteins shares homology clustered within four conserved regions termed BCL-2 homology 1 through 4 (BH1-4). These novel domains control the ability of these proteins to dimerize and function. An amphipathic alpha helix, BH3, is of particular importance for the proapoptotic family members. BID and BAD represent an evolving set of proapoptotic molecules, which bear sequence homology only at BH3. They appear to reside more proximal in the pathway serving as death ligands. BAD connects upstream signal transduction paths with the BCL-2 family, modulating this checkpoint for apoptosis. In the presence of survival factor interleukin-3, cells phosphorylate BAD on two serine residues. This inactivated BAD is held by the 14-3-3 protein, freeing BCL-XL and BCL-2 to promote survival. Activation of BAX results in the initiation of apoptosis. Downstream events in this program include mitochondrial dysfunction, as well as Caspase activation. The pro- and antiapoptotic BCL-2 family members represent central regulators in an evolutionarily conserved pathway of cell death. Aberrations in the BCL-2 family result in disordered homeostasis, a pathogenic event in diseases, including cancer.