The antioxidant function of the p53 tumor suppressor

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Abstract

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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Figure 1: Effect of p53 status on intracellular ROS.
Figure 2: Activity of p53 is required for maintaining functional state of several genes with antioxidant products.
Figure 3: Opposite effects of p53 on ROS levels.
Figure 4: Antioxidant effect of p53 after mild stress and pro-oxidant effect of p53 after grave stress.
Figure 5: p53 decreases DNA oxidation and mutagenesis.
Figure 6: Elevated ROS in p53-negative (sip53) tumors and in Trp53−/− mice contribute to accelerated tumor growth, karyotype instability and lymphomagenesis.

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Acknowledgements

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.

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Correspondence to Peter M Chumakov.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Characterization of RKO cells with inhibited expression of p53. (PDF 88 kb)

Supplementary Fig. 2

Effect of deficiency in p53 on intracellular ROS level. (PDF 17 kb)

Supplementary Fig. 3

Effect of overexpressed p53-regulated genes on intracellular ROS level. (PDF 59 kb)

Supplementary Fig. 4

Effect of p53 expression on cell cycle and apoptosis in H1299 cells. (PDF 51 kb)

Supplementary Fig. 5

Effect of p53 overexpression on intracellular ROS levels in control and mitochondrial DNA-deficient cells (p0). (PDF 73 kb)

Supplementary Fig. 6

Inhibition of p53 in RKO cells affects the response to moderate and high levels of H2O2. (PDF 204 kb)

Supplementary Fig. 7

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)

Supplementary Fig. 8

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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