ABSTRACT
Members of the bcl-2 gene family play a central role in regulating the relative sensitivity and resistance of cells to a wide variety of apoptotic stimuli. The first member of this multigene family, bcl-2, was discovered by virtue of its involvement in the t(14;18) chromosomal translocations commonly found in lymphomas [1-4]. Deregulation of the bcl-2 gene either by translocations in B-cell lymphomas or by other mechanisms in several other types of cancer contributes to neoplastic cell expansion by prolonging cell survival rather than by accelerating rates of cell division [5-8]. The Bcl-2 protein also can protect tumor cells from apoptosis induced by radiation and nearly all cytotoxic anticancer drugs [9-12], thus contributing to treatment failures in patients with cancer [13-16]. In addition to cytogenetic and molecular studies of human cancers which have suggested that bcl-2 represents a critical point of regulation of apoptotic processes in cells, hints of the central importance of bcl-2 as a regulator of programmed cell death have come from investigations of the genetics of developmental cell death in lower organisms as well as from viral genetics, where homologs of bcl-2 have been discovered such as the ced-9 gene in the nematode C. elegans [17] and the BHRF-1 and E1b-19 kDa proteins in Epstein-Barr virus and adenovirus, respectively [18-20]. Several additional homologs of bcl-2 have recently been discovered in mammals, including humans, revealing the presence of a multigene family [21-24]. Interestingly, some members of the bcl-2 gene family function as inhibitors of cell death, similar to bcl-2, whereas others are enhancers of apoptosis that oppose the actions of the Bcl-2 protein. Many of these Bcl-2 family proteins have the capacity to interact with each other through formation of homo-and heterotypic dimers [21, 25], revealing an important role for protein-protein interactions in the orchestration of Bcl-2 family protein function and suggesting approaches to pharmacologically manipulating the physiological cell death pathway.
