BCL-XS AND BAD POTENTIATE THE DEATH SUPPRESSING ACTIVITIES OF BCL-XL,BCL-2, AND A1 IN YEAST

Members of the Bc1-2 family can be grouped into three classes based up on their effects on cell death. The first class suppresses death and i ncludes Bcl-2. A second group which includes Bar, is lethal, whereas a third class, including Bcl-xS, potentiates killing although the membe rs are not lethal by themselves. The proteins in the last class ape pr oposed to exert their activity by binding to anti-apoptotic family mem bers, thereby making the cell more susceptible to killing by another a gent. To test this hypothesis, an inducible yeast expression system is reported that permits the functional analysis of three Bcl-2 family m embers, in yeast, Bar is lethal, and this activity is suppressed by Bc l-xL, Bcl-2, and Al. Co-expression of Bcl-xS did not diminish the abil ity of any of the anti-apoptotic members to antagonize Bar. Rather, co -expression of Bcl-xS potentiated the anti-death activity of all three proteins. This effect was not the result of changes in either the lev els or integrity of Bar or anti-apoptotic proteins. Thus, Bcl-xS can b ind to anti-apoptotic family members, but this association does not re sult in loss of biological activity. Therefore, Bcl-xS may act downstr eam of Bar and in a pathway that is conserved in yeast.