Abstract
The nuclear transcription factor p53, discovered in 1979, has a broad range of biological functions, primarily the regulation of apoptosis, the cell cycle, and DNA repair. In addition to these canonical functions, a growing body of evidence suggests that p53 plays an important role in regulating intracellular redox homeostasis through transcriptional and nontranscriptional mechanisms. Oxidative stress induction and p53 activation are common responses to chemical exposure and are suggested to play critical roles in chemical-induced toxicity. The activation of p53 can exert either prooxidant or antioxidant activity, depending on the context. In this review, we discuss the functional role of p53 in regulating chemical-induced oxidative stress, summarize the potential signaling pathways involved in p53's regulation of chemically mediated oxidative stress, and propose issues that should be addressed in future studies to improve understanding of the relationship between p53 and chemical-induced oxidative stress.
Highlights
An imbalance in the oxidation reduction system in favor of oxidants is known to cause oxidative stress, a condition that is characterized by the overproduction of reactive oxygen species (ROS) and/or decreased antioxidative capacity [1, 2]
ROS generation is mainly due to excessive stimulation of NAD(P)H oxidases or the oxidative energy metabolism in mitochondria [3]
Previous research has shown that the inhibition of p53 by RNAi results in significantly ameliorated ROS generation, accompanied by a decrease in the extent of DNA damage and apoptosis induced by patulin in human embryonic kidney (HEK) 293 cells, indicating the contribution of p53 to patulin-induced oxidative stress [12]
Summary
An imbalance in the oxidation reduction (redox) system in favor of oxidants is known to cause oxidative stress, a condition that is characterized by the overproduction of reactive oxygen species (ROS) and/or decreased antioxidative capacity [1, 2]. The oxidative stress-related enzymes include superoxide dismutases (SODs) [17], catalase [18], glutathione peroxidase (GPx) [19], heme oxygenase-1 (HO-1) [20], thioredoxins (TRXs) [21], peroxiredoxins (PRXs) [22], glutaredoxins [23], cytochromes P450 (CYPs), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [7, 24]. The primary functions of p53 include the regulation of cell cycle and apoptosis and the promotion of DNA repair [31]. In addition to these canonical activities, there is increasing evidence to suggest that p53 contributes to a number of noncanonical functions, such as the regulation of redox balance, glucose metabolism, and autophagy. HeLa cells, A431 cells (lacked functional p53), 50 μM, 12 h
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