The critical role of catalase in prooxidant and antioxidant function of p53.
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.
DNA Damage Response Network Center, Chosun University School of Medicine, Gwangju, South Korea.
M Y
MY
Kang
H-B
HB
Kim
C
C
Piao
K H
KH
Lee
J W
JW
Hyun
I-Y
IY
Chang
H J
HJ
You
D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012264:Ribonucleotide Reductases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000975:Antioxidants; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; C411296:TP53I3 protein, human; D016159:Tumor Suppressor Protein p53; D002374:Catalase; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases