BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak

The BH3-only proteins Bim and Bad bind to the anti-apoptotic Bcl-2 proteins and induce apoptosis in wildtype cells and cells from either bax(-/-) or b ak(-/-) animals. In contrast, constitutively active forms of Bim and Bad fa iled to induce apoptosis in bax(-/-)bak(-/-) cells. Expression of Bar resto red susceptibility of the cells to Bim and Bad. In addition, Bar but not Bi m or Bad sensitized the bax(-/-)bak(-/-) cells to a wide variety of cell de ath stimuli including UV irradiation, chemotherapeutic agents, and ER stres s. These results suggest that neither activation of BH3-only proteins nor s uppression of pro-survival Bcl-2 proteins is sufficient to kill cells in th e absence of both Bar and Bak. Furthermore, whereas mouse embryo fibroblast s (MEF) expressing only Bar or Bak displayed resistance to transformation, bax(-/-)bak(-/-) MEF were nearly as prone to oncogenic transformation as p5 3(-/-) MEF. Thus, the function of either Bax or Bak appears required to ini tiate most forms of apoptosis and to suppress oncogenic transformation.