REACTIVE OXYGEN SPECIES ARE DOWNSTREAM MEDIATORS OF P53-DEPENDENT APOPTOSIS

Reactive oxygen species (ROS) have been implicated as potential modula tors of apoptosis. Conversely, experiments under hypoxic conditions ha ve suggested that apoptosis could occur in the absence of ROS. We soug ht to determine whether a central modulator of apoptosis, p53, regulat es the levels of intracellular ROS and whether a rise in ROS levels is required for the induction of p53-dependent apoptosis. We transiently overexpressed wild-type p,53, using adenoviral gene transfer, and ide ntified cell types that were sensitive or resistant to p53-mediated ap optosis. Cells sensitive to p53-mediated apoptosis produced ROS concom itantly with p53 overexpression, whereas cells resistant to p53 failed to produce ROS. In sensitive cells, both ROS production and apoptosis were inhibited by antioxidant treatment. These results suggest that p 53 acts to regulate the intracellular redox state and induces apoptosi s by a pathway that is dependent on ROS production.