It is widely accepted that the p53 tumor suppressor restricts abnormal cells by induction of growth arrest or by triggering apoptosis. Here we show that, in addition, p53 protects the genome from oxidation by reactive oxygen species (ROS), a major cause of DNA damage and genetic instability. In the absence of severe stresses, relatively low levels of p53 are sufficient for upregulation of several genes with antioxidant products, which is associated with a decrease in intracellular ROS. Downregulation of p53 results in excessive oxidation of DNA, increased mutation rate and karyotype instability, which are prevented by incubation with the antioxidant N-acetylcysteine (NAC). Dietary supplementation with NAC prevented frequent lymphomas characteristic of Trp53-knockout mice, and slowed the growth of lung cancer xenografts deficient in p53. Our results provide a new paradigm for a nonrestrictive tumor suppressor function of p53 and highlight the potential importance of antioxidants in the prophylaxis and treatment of cancer.
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Lane, D.P. p53, guardian of the genome. Nature 358, 15–16 (1992).
Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47–95 (2002).
Finkel, T. Oxidant signals and oxidative stress. Curr. Opin. Cell Biol. 15, 247–254 (2003).
Jackson, A.L. & Loeb, L.A. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat. Res. 477, 7–21 (2001).
Klungland, A. et al. Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc. Natl. Acad. Sci. USA 96, 13300–13305 (1999).
Beckman, K.B. & Ames, B.N. Oxidative decay of DNA. J. Biol. Chem. 272, 19633–19636 (1997).
Macip, S. et al. Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol. Cell. Biol. 23, 8576–8585 (2003).
Polyak, K., Xia, Y., Zweier, J.L., Kinzler, K.W. & Vogelstein, B. A model for p53-induced apoptosis. Nature 389, 300–305 (1997).
Tan, M. et al. Transcriptional activation of the human glutathione peroxidase promoter by p53. J. Biol. Chem. 274, 12061–12066 (1999).
Hussain, S.P. et al. p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Res. 64, 2350–2356 (2004).
Yoon, K.A., Nakamura, Y. & Arakawa, H. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J. Hum. Genet. 49, 134–140 (2004).
Budanov, A.V., Sablina, A.A., Feinstein, E., Koonin, E.V. & Chumakov, P.M. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304, 596–600 (2004).
Agarwal, M.L., Agarwal, A., Taylor, W.R. & Stark, G.R. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc. Natl. Acad. Sci. USA 92, 8493–8497 (1995).
Ossovskaya, V.S. et al. Use of genetic suppressor elements to dissect distinct biological effects of separate p53 domains. Proc. Natl. Acad. Sci. USA 93, 10309–10314 (1996).
Florenes, V.A. et al. MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. J. Natl. Cancer Inst. 86, 1297–1302 (1994).
Velasco-Miguel, S. et al. PA26, a novel target for the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene 18, 127–137 (1999).
Lin, J., Chen, J., Elenbaas, B. & Levine, A.J. Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. Genes Dev. 8, 1235–1246 (1994).
Osovskaia, V.S. et al. Effect of on various cell lines of p53 cDNA, expressed under the control of an exogenous homologous promotor. Mol Biol (Mosk) 29, 61–70 (1995).
Kovar, H. et al. Characterization of distinct consecutive phases in non-genotoxic p53-induced apoptosis of Ewing tumor cells and the rate-limiting role of caspase 8. Oncogene 19, 4096–4107 (2000).
King, M.P. & Attardi, G. Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA. Cell 52, 811–819 (1988).
Griffiths, S.D. et al. Absence of p53 permits propagation of mutant cells following genotoxic damage. Oncogene 14, 523–531 (1997).
Havre, P.A., Yuan, J., Hedrick, L., Cho, K.R. & Glazer, P.M. p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. Cancer Res. 55, 4420–4424 (1995).
Bishop, A.J. et al. Atm-, p53-, and Gadd45a-deficient mice show an increased frequency of homologous recombination at different stages during development. Cancer Res. 63, 5335–5343 (2003).
Knaap, A.G. & Simons, J.W. A mutational assay system for L5178Y mouse lymphoma cells, using hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT)-deficiency as marker. The occurrence of a long expression time for mutations induced by X-rays and EMS. Mutat. Res. 30, 97–110 (1975).
Donehower, L.A. et al. Effects of genetic background on tumorigenesis in p53-deficient mice. Mol. Carcinog. 14, 16–22 (1995).
Donehower, L.A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).
Wahl, G.M., Linke, S.P., Paulson, T.G. & Huang, L.C. Maintaining genetic stability through TP53 mediated checkpoint control. Cancer Surv. 29, 183–219 (1997).
Fukasawa, K., Wiener, F., Vande Woude, G.F. & Mai, S. Genomic instability and apoptosis are frequent in p53 deficient young mice. Oncogene 15, 1295–1302 (1997).
Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).
Zurer, I. et al. The role of p53 in base excision repair following genotoxic stress. Carcinogenesis 25, 11–19 (2004).
Seo, Y.R. & Jung, H.J. The potential roles of p53 tumor suppressor in nucleotide excision repair (NER) and base excision repair (BER). Exp. Mol. Med. 36, 505–509 (2004).
Achanta, G. & Huang, P. Role of p53 in sensing oxidative DNA damage in response to reactive oxygen species-generating agents. Cancer Res. 64, 6233–6239 (2004).
Deng, C., Zhang, P., Harper, J.W., Elledge, S.J. & Leder, P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684 (1995).
Villunger, A. et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302, 1036–1038 (2003).
Jeffers, J.R. et al. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4, 321–328 (2003).
Kim, H.J. et al. Modulation of redox-sensitive transcription factors by calorie restriction during aging. Mech. Ageing Dev. 123, 1589–1595 (2002).
Sohal, R.S., Agarwal, S., Candas, M., Forster, M.J. & Lal, H. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech. Ageing Dev. 76, 215–224 (1994).
Hursting, S.D., Perkins, S.N. & Phang, J.M. Calorie restriction delays spontaneous tumorigenesis in p53-knockout transgenic mice. Proc. Natl. Acad. Sci. USA 91, 7036–7040 (1994).
Hursting, S.D. et al. Diet-gene interactions in p53-deficient mice: insulin-like growth factor-1 as a mechanistic target. J. Nutr. 134, 2482S–2486S (2004).
Fukasawa, K., Choi, T., Kuriyama, R., Rulong, S. & Vande Woude, G.F. Abnormal centrosome amplification in the absence of p53. Science 271, 1744–1747 (1996).
Agapova, L.S. et al. Chromosome changes caused by alterations of p53 expression. Mutat. Res. 354, 129–138 (1996).
Reliene, R., Fischer, E. & Schiestl, R.H. Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice. Cancer Res. 64, 5148–5153 (2004).
Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996).
Schubert, R. et al. Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice. Hum. Mol. Genet. 13, 1793–1802 (2004).
Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).
Li, F.P. et al. Recommendations on predictive testing for germ line p53 mutations among cancer-prone individuals. J. Natl. Cancer Inst. 84, 1156–1160 (1992).
Bond, G.L. et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602 (2004).
Neumann, C.A. et al. Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature 424, 561–565 (2003).
Balansky, R., Izzotti, A., Scatolini, L., D'Agostini, F. & De Flora, S. Induction by carcinogens and chemoprevention by N-acetylcysteine of adducts to mitochondrial DNA in rat organs. Cancer Res. 56, 1642–1647 (1996).
We thank B. Kopnin for support of in vivo experiments, and G. Stark, A. Levine and A. Gudkov for criticism during preparation of the manuscript. The work was supported by US National Institutes of Health grants R01 CA10490 and R01 AG025278 to P.M.C.
The authors declare no competing financial interests.
Characterization of RKO cells with inhibited expression of p53. (PDF 88 kb)
Effect of deficiency in p53 on intracellular ROS level. (PDF 17 kb)
Effect of overexpressed p53-regulated genes on intracellular ROS level. (PDF 59 kb)
Effect of p53 expression on cell cycle and apoptosis in H1299 cells. (PDF 51 kb)
Effect of p53 overexpression on intracellular ROS levels in control and mitochondrial DNA-deficient cells (p0). (PDF 73 kb)
Inhibition of p53 in RKO cells affects the response to moderate and high levels of H2O2. (PDF 204 kb)
Effect of p53 deficiency on DNA oxidation level and mutation rate and xenograft growth of A549 cells with knockdown of p53 or Hi95. (PDF 34 kb)
N-acetylcysteine does not affect growth of p53-positive and p53-negative RKO cells in vitro. (PDF 31 kb)
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Sablina, A., Budanov, A., Ilyinskaya, G. et al. The antioxidant function of the p53 tumor suppressor. Nat Med 11, 1306–1313 (2005) doi:10.1038/nm1320
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