THE ABILITY OF BCL-X(L) AND BCL-2 TO PREVENT APOPTOSIS CAN BE DIFFERENTIALLY REGULATED

Although expression of Bcl-2 has been shown to prevent apoptosis under many circumstances, there are several systems in which Bcl-2 fails to promote cell survival. We have previously reported that Bcl-2 and Bcl -x(L) display differential ability to protect WEHI-231 cells from mult iple inducers of apoptosis. A possible explanation for this paradox wa s provided by the discovery of Bar. Bar is a Bcl-2-related protein whi ch can inhibit the ability of Bcl-2 to enhance the survival of growth factor-dependent cell lines in the absence of growth factor. Consisten t with the possibility that Bcl-2 function in WEHI-231 cells is inhibi ted by Bar, WEHI-231 cells were found to express a high level of Bar. To directly test the effects of Bar expression on Bcl-x(L) function, F L5.12 cells were transfected with both genes. Although Bar overexpress ion can inhibit Bcl-2 from prolonging cell survival upon growth factor withdrawal, Bar overexpression did not inhibit Bel-x(L) from preventi ng apoptosis in this cell line. Although Bcl-2 and Bcl-x(L) were both found to be able to form heterodimers with Bar, the majority of Bar in both cases was not complexed to a partner. Our data suggest that Bcl- x(L) does not function by simply preventing the formation of Bar homod imers which promote cell death. Instead Bar appears to display selecti vity in its ability to inhibit Bcl-2 but not Bcl-x(L) from prolonging survival. Furthermore, our data suggest that the abilities of Bcl-2 an d Bcl-x(L) to promote cell survival are not identical and can be indep endently regulated within a cell. Regulation of a cell's apoptotic thr eshold is likely to result from a complex set of interactions among Bc l-2 family members and other, as yet uncharacterised, regulators of ap optosis.