Reactive oxygen species are downstream mediators of p53-dependent apoptosis.

Abstract

Reactive oxygen species (ROS) have been implicated as potential modulators of apoptosis. Conversely, experiments under hypoxic conditions have suggested that apoptosis could occur in the absence of ROS. We sought to determine whether a central modulator of apoptosis, p53, regulates 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 p53, using adenoviral gene transfer, and identified cell types that were sensitive or resistant to p53-mediated apoptosis. Cells sensitive to p53-mediated apoptosis produced ROS concomitantly 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 p53 acts to regulate the intracellular redox state and induces apoptosis by a pathway that is dependent on ROS production.

Camptothecin induced mitochondrial dysfunction leading to programmed cell death in unicellular hemoflagellate Leishmania donovani

“…This increase in the level of lipid peroxidation causes the loss of mitochondrial membrane potential, observed after treatment with CPT for 2.5 h. These results are consistent with those of other investigators, who concluded that lipid peroxidation and oxidative stress together may impair a variety of intra-and extramitochondrial membrane transport systems that may contribute to apoptosis. 28,38 In mammalian cells, an increase in cellular ROS production has been observed in an apoptotic process triggered by various stimuli, 33,39,40 and has been claimed to be responsible for the depolarization of Dc m and subsequent cell death. 33,39,41 Furthermore, some authors suggest that ROS generation precedes caspase activation, 33,38 whereas others claim that it is a consequence.…”

Role of redox potential and reactive oxygen species in stress signaling

“…Thus, a Ref1-thioredoxin complex may also participate in the regulation of p53 by ROS. The role of ROS in p53-mediated apoptosis has been demonstrated (Johnson et al, 1996). Furthermore, an increased tumor cells capacity for undergoing apoptosis in response to ROS was also shown to be p53-dependent (Graeber et al, 1996).…”

True

“…33 In addition, p53 might be responsible for the generation of ROS. 34 Furthermore, several direct lines of evidence imply that the pro-apoptotic activity of p53 might be independent of its function as a transcription factor. 35,36 The pathways whereby p53 leads to execution of apoptotic program seem to be multiple and may strongly depend on the cell type and the nature of apoptotic stimuli.…”

“…In particular, the role of ROS and Bax as well as mitochondrial cytochrome c release as downstream mediators in the anti-cancer drug-induced apoptosis and in the models of apoptosis induced by transient p53-overexpression have been recently controversially discussed. 3,34,[37][38][39] In the model of ROS-driven apoptosis, the generation of ROS has been suggested as a primary regulatory component followed by the activation of caspases and caspase-dependent loss of MMP. 34,38 Consequently, this form of cell death could be prevented by antioxidants.…”

“…3,34,[37][38][39] In the model of ROS-driven apoptosis, the generation of ROS has been suggested as a primary regulatory component followed by the activation of caspases and caspase-dependent loss of MMP. 34,38 Consequently, this form of cell death could be prevented by antioxidants. However, in our study, ROS levels only slightly increased in HHT-treated cells.…”