bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death

Abstract

We report the isolation of bcl-x, a bcl-2-related gene that can function as a bcl-2-independent regulator of programmed cell death (apoptosis). Alternative splicing results in two distinct bcl-x mRNAs. The protein product of the larger mRNA, bcl-xL, is similar in size and predicted structure to Bcl-2. When stably transfected into an IL-3-dependent cell line, bcl-xL inhibits cell death upon growth factor withdrawal at least as well as bcl-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 cells. 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, bcl-xL is found in tissues containing long-lived postmitotic cells, such as adult brain. Together these data suggest that bcl-x plays an important role in both positive and negative regulation of programmed cell death.

Molecular requirements for doxorubicin-mediated death in murine oocytes

“…Briefly, we performed RT-PCR with specific primers spanning the alternative splice site of the bcl-x gene. 38 Aliquots of five oocytes were removed at harvesting, and after 6, 12 and 20 h of DXR exposure. Each aliquot was lysed in 50 ml of GT solution, and total nucleic acid was recovered by ethanol precipitation using glycogen as a carrier, and RT-PCR was then performed as previously described.…”

GRS, a novel member of the Bcl-2 gene family, is highly expressed in multiple cancer cell lines and in normal leukocytes

“…This implies the existence of other gene family members also involved in the regulation of apoptosis. A number of other cellular proteins including Bax (Oltvai et al, 1993), Bcl-x (Boise et al, 1993), Bak (Chittenden et al, 1995;Kiefer et al, 1995), Mcl-1 (Kozopas et al, 1993) and A1 (Lin et al, 1993) share highly conserved domains (BH-1 and BH-2; Oltvai et al, 1993) with Bcl-2. Bax is capable of forming homodimers and heterodimers with Bcl-2.…”

“…Therefore the ratio of Bcl-2 to Bax regulates the apoptotic response of the cell. The Bcl-x gene produces two proteins by alternative splicing, Bcl-x S which promotes and Bcl-x L which inhibits apoptosis (Boise et al, 1993). Recently Choi et al (1995) described a new member of the Bcl-2 gene family, B¯-1 isolated from human fetal liver.…”

v-Abl protein tyrosine kinase (PTK) mediated suppression of apoptosis is associated with the up-regulation of Bcl-XL

“…Whether various survival stimuli (such as growth factors and interactions with appropriate extracellular matrices) share common downstream signalling elements that impinge upon, and suppress, the default apoptotic pathway is not known. One family of proteins known to play a central role in regulating the threshold at which spontaneous or damage induced apoptosis is engaged is the Bcl-2 family (Korsmeyer, 1992;Yang and Korsmeyer, 1996) comprised of suppressors of apoptosis including Bcl-2 (Vaux et al, 1988) and Bclx L (Boise et al, 1993) and the accelerators, Bax (Oltvai et al, 1993), Bad (Yang et al, 1995), Bak, (Farrow et al, 1995) and Bik (Boyd et al, 1995). An attractive model suggests that the ratio of homodimers to heterodimers within the family predicts cell fate (Reed, 1995, Yang andKorsmeyer, 1996).…”