The antioxidant function of the p53 tumor suppressor.
Journal: 2006/May - Nature Medicine
ISSN: 1078-8956
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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Nat Med 11(12): 1306-1313

The antioxidant function of the p53 tumor suppressor

Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
Cancer Research Center, Kashirskoye Road 24, 115478 Moscow, Russia
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Street 32, 119991 Moscow, Russia
Correspondence should be addressed to P.M.C. (gro.fcc@pkamuhc).
Present address: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston MA 02115, USA
Present address: University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA
These authors contributed equally to this work.

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 for DNA damage and genetic instability. In the absence of severe stresses relatively low levels of p53 are sufficient for up-regulation of several antioxidant genes, which is associated with a decrease in intracellular ROS. Down-regulation of p53 results in excessive oxidation of DNA, increased mutation rate, and karyotype instability, which are prevented by incubation with antioxidant N-acetylcysteine (NAC). Dietary supplementation with NAC prevents frequent lymphomas characteristic to p53 knockout mice, and slows down growth of xenografts from A549 cells with p53 inhibited by siRNA. Our results provide novel paradigm for a non-restrictive tumor suppressor function of p53 and highlight potential importance of antioxidants in prophylactics and treatment of cancer.

Abstract

The major function for the p53 tumor suppressor is to restrict abnormal or stress-exposed cells before damage to DNA is converted to inherited mutation1. However, even without extended stress the DNA is exposed to endogenous damaging reactive oxygen species (ROS), which are by-products of normal respiration, and important signaling molecules23. Indeed, endogenous ROS is the major source of DNA damage4, and a substantial factor contributing to chromosome instability and accumulation of mutations and deletions leading to cancer45. As the endogenous ROS modify approximately 20,000 bases of DNA per day in a single cell6 it is unlikely that the restriction of proliferation of cells with oxidized DNA would be efficient in preventing mutations. Previously it was found that among transcriptional targets of p53 there are several potential ROS-generating genes whose action presumably contributes to p53-mediated cell death78. However, other p53-upregulated genes, such as glutathione peroxidase (GPX1) 910, Mn-superoxide dismutase (Mn-SOD)10 and aldehyde dehydrogenase 4 (ALDH4)11, would presumably act as antioxidants. In addition, the function of two p53-regulated sestrins (HI95 and PA26) is essential for regeneration of over-oxidized peroxiredoxins12, the enzymes involved in the decomposition of hydrogen peroxide3. These findings suggest that p53 might play opposite roles in ROS regulation. In this study we discriminate between pro- and antioxidant functions of p53, and establish a substantial contribution of p53-mediated antioxidant mechanisms in the control of genetic stability and cancer prevention.

Footnotes

COMPETING INTERESTS STATEMENT

The authors declare that they have no competing financial interests.

Footnotes

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