bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis

Inactivation of p53-dependent apoptosis promotes oncogenic transformation, tumor development, and resistance to many cytotoxic anticancer agents, p53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis, To determine whether bax is required for p53-dependent apoptosis, the effects of bax deficiency were examined in primary 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 contributes 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 determinant of p53-dependent chemosensitivity and illustrate how p53 can promote apoptosis by coordinating the activities of multiple effecters.