Bcl-x Antagonizes the Protective Effects of Bcl-x

Bcl-x, a member of the Bcl-2 family, has two alternatively spliced forms, Bcl-x and Bcl-x . Bcl-x , like Bcl-2, is able to protect cells from a wide variety of apoptotic stimuli. Bcl-x , as a result of alternative splicing, lacks 63 amino acids that comprise the region of greatest amino acid identity between Bcl-x and Bcl-2. These amino acids contain the highly conserved BH1 and BH2 regions, which have been used to define the Bcl-2 family. We show that both Bcl-x and Bcl-x are able to regulate cell survival in a dose-dependent fashion. Bcl-x is able to increase the cellular apoptotic threshold and is able to form stable complexes with Bax both in vitro and in vivo . In contrast, Bcl-x can effectively inhibit the protective effects of Bcl-x following growth factor withdrawal and chemotherapeutic drug treatment. However, compared with Bax, Bcl-x binds to Bcl-x weakly when assessed by in vitro binding assays. Coimmunoprecipitation from mammalian cells demonstrates that Bcl-x does not show an observable ability to form heterodimers with other Bcl-2 family members. In addition, overexpression of Bcl-x does not alter the ability of Bax to heterodimerize with Bcl-x in vivo . Thus, Bcl-x does not appear to function by competitively disrupting the formation of dimers composed of other Bcl-2 family members. This suggests that Bcl-x can enhance cellular sensitivity to apoptosis via a mechanism of action distinct from other Bcl-2 family members that promote apoptosis.