Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species.
Uncontrolled accumulation of reactive oxygen species (ROS) causes oxidative stress and induces harmful effects. Both high ROS levels and p53 mutations are frequent in human cancer. Mutant p53 forms are known to actively promote malignant growth. However, no mechanistic details are known about the contribution of mutant p53 to excessive ROS accumulation in cancer cells. Herein, we examine the effect of p53(R273H), a commonly occurring mutated p53 form, on the expression of phase 2 ROS-detoxifying enzymes and on the ability of cells to readopt a reducing environment after exposure to oxidative stress. Our data suggest that p53(R273H) mutant interferes with the normal response of human cells to oxidative stress. We show here that, upon oxidative stress, mutant p53(R273H) attenuates the activation and function of NF-E2-related factor 2 (NRF2), a transcription factor that induces the antioxidant response. This effect of mutant p53 is manifested by decreased expression of phase 2 detoxifying enzymes NQO1 and HO-1 and high ROS levels. These findings were observed in several human cancer cell lines, highlighting the general nature of this phenomenon. The failure of p53(R273H) mutant-expressing cells to restore a reducing oxidative environment was accompanied by increased survival, a known consequence of mutant p53 expression. These activities are attributable to mutant p53(R273H) gain of function and might underlie its well-documented oncogenic nature in human cancer.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100,  Israel.
Eyal
E
Kalo
Ira
I
Kogan-Sakin
Hilla
H
Solomon
Elad
E
Bar-Nathan
Moshe
M
Shay
Yoav
Y
Shetzer
Elya
E
Dekel
Naomi
N
Goldfinger
Yossi
Y
Buganim
Perry
P
Stambolsky
Ido
I
Goldstein
Shalom
S
Madar
Varda
V
Rotter
D019943:Amino Acid Substitution / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008298:Maleates / Q000494:pharmacology; D050217:Metabolic Detoxication, Phase II / Q000235:genetics*; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D008298:Maleates; D050505:Mutant Proteins; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D013481:Superoxides; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C014476:diethyl maleate