BAD, A HETERODIMERIC PARTNER FOR BCL-X(L) AND BCL-2, DISPLACES BAX AND PROMOTES CELL-DEATH

To extend the mammalian cell death pathway, we screened for further Bc l-2 interacting proteins, Both yeast two-hybrid screening and lambda e xpression cloning identified a novel interacting protein, Bad, whose h omology to Bcl-2 is limited to the BH1 and BH2 domains, Bad selectivel y dimerized with Bcl-X(L) as well as Bcl-2, but not with Bar, Bcl-X(S) , Mcl-1, A1, or itself, Bad binds more strongly to Bcl-X(L) than Bcl-2 in mammalian cells, and it reversed the death repressor activity of B cl-X(L), but not that of Bcl-2, When Bad dimerized with Bcl-X(L), Bar was displaced and apoptosis was restored, When approximately half of B ax was heterodimerized, death was inhibited. The susceptibility of a c ell to a death signal is determined by these competing dimerizations i n which levels of Bad influence the effectiveness of Bcl-2 versus Bcl- X(L) in repressing death.