The critical role of catalase in prooxidant and antioxidant function of p53

Abstract

The tumor suppressor p53 is an important regulator of intracellular reactive oxygen species (ROS) levels, although downstream mediators of p53 remain to be elucidated. Here, we show that p53 and its downstream targets, p53-inducible ribonucleotide reductase (p53R2) and p53-inducible gene 3 (PIG3), physically and functionally interact with catalase for efficient regulation of intracellular ROS, depending on stress intensity. Under physiological conditions, the antioxidant functions of p53 are mediated by p53R2, which maintains increased catalase activity and thereby protects against endogenous ROS. After genotoxic stress, high levels of p53 and PIG3 cooperate to inhibit catalase activity, leading to a shift in the oxidant/antioxidant balance toward an oxidative status, which could augment apoptotic cell death. These results highlight the essential role of catalase in p53-mediated ROS regulation and suggest that the p53/p53R2-catalase and p53/PIG3-catalase pathways are critically involved in intracellular ROS regulation under physiological conditions and during the response to DNA damage, respectively. Reactive oxygen species (ROS) are generated as products or by-products in cells and function as signaling molecules and cellular toxicants.1,2 Therefore, a series of antioxidant mechanisms maintain and protect intracellular redox homeostasis.2-4 A shift in the balance between oxidants and antioxidants toward oxidation causes DNA mutations, protein oxidation, and lipid peroxidation, which eventually lead to loss of molecular function 1,2,5 and contribute to the pathogenesis of human diseases, including aging and cancer. 3The p53 protein has been proposed as a critical regulator of intracellular ROS levels. Upon activation following DNA damage, p53 can activate several genes that result in increased ROS generation, which contributes to the induction of apoptosis in cells with unrepaired DNA damage.6-10 The induction of apoptosis is central to the tumor-suppressive activity of p53. 11,12 By using the serial analysis of gene expression technique to evaluate the patterns of gene expression following p53 expression, a series of p53-inducible genes (PIG genes) have been identified that are predicted to encode proteins that could generate ROS. 8 Of particular interest is p53-inducible gene 3 (PIG3), which shares sequence similarity with NADPH-quinine oxidoreductase, and is induced by p53 before the onset of apoptosis and contributes to ROS generation.8 Thus, PIG3 is believed to be one of the major factors involved in p53-induced apoptosis through ROS generation. This was the first clear connection between p53 and ROS generation, but the molecular mechanisms of PIG3-induced ROS generation have not yet been elucidated. Under physiological condition, basal levels of p53 can also upregulate antioxidant genes that function to lower ROS levels, and this antioxidant function of p53 is important in preventing oxidative stress-induced DNA damage and tumor development under low-stress conditions.13-21 Thus, p53 has opposing roles in ...

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Inhibiting Protein Arginine Deiminases Has Antioxidant Consequences

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