BAX-DEFICIENCY PROMOTES DRUG-RESISTANCE AND ONCOGENIC TRANSFORMATION BY ATTENUATING P53-DEPENDENT APOPTOSIS

Inactivation of p53-dependent apoptosis promotes oncogenic transformat ion, tumor development, and resistance to many cytotoxic anticancer ag ents, p53 can transcriptionally activate bax, a bcl-2 family member th at promotes apoptosis, To determine whether bax is required for p53-de pendent apoptosis, the effects of bax deficiency were examined in prim ary fibroblasts expressing the EIA oncogene, a setting where apoptosis is dependent on endogenous p53, We demonstrate that bax can function as an effector of p53 in chemotherapy-induced apoptosis and contribute s to a p53 pathway to suppress oncogenic transformation, Furthermore, we show that additional p53 effecters participate in these processes. These p53-controlled factors act synergistically with Bax to promote a full apoptotic response, and their action is suppressed by the Bcl-2 and E1B 19K oncoproteins. These studies demonstrate that Bax is a dete rminant of p53-dependent chemosensitivity and illustrate how p53 can p romote apoptosis by coordinating the activities of multiple effecters.