We report the isolation of b&x, a b&2-related gene that can function as a bcl-24ndependent regulator of programed ceil death (apoptosis). Alternative splicing results in two distinct b&x mRNAs. The protein product of the larger mRNA, bcl-XL, is similar in size and predicted structure to Bci-2. When stably transfected into an IL-3-dependent ceil line, b&xl. inhibits cell death upon growth factor withdrawal at least as well as b&2. Surprisingly, the second mRNA species, bcl-xs, encodes a protein that inhibits the ability of bcl-2 to enhance the survival of growth factor-deprived ceils. In vivo, bcl-xs mRNA is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, b&XL is found in tissues containing long-lived postmitotic ceils, such as adult brain. Together these data suggest that b&x plays an important role in both positive and negative regulation of programed ceil death.

The control of cell number in muiticeiiuiar eukaryotes represents a balance between ceil proliferation and cell death. Although a great deal has been learned in recent years about the regulation of ceil proliferation, relatively little is known about the regulation of cell death (for reviews see Ellis et al., 1991; Raff, 1992). Recently, attention has begun to focus on the mechanisms that regulate programed ceil death (apoptosis)(Williams, 1991). Apoptosis is an active process by which many ceils die during deveiopmerit and self-maintenance in complex eukaryotes (Kerr et al., 1972). Cell death by apoptosis occurs when a ceil activates an internally encoded suicide program as a result of either extrinsic or intrinsic signals. Apoptotic cell death is characterized by plasma membrane biebbing, cell volume loss, nuclear condensation, and endonucleoiy-tic degradation of DNA at nucieosomal intervals (Wyilie et al., 1960).