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PMID: 16286925 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

The antioxidant function of the p53 tumor suppressor.

Nature medicine ·Vol. 11 ·No. 12 ·2005-12-00 ·Pages 1306-13

Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM

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.

MeSH Terms
8-Hydroxy-2'-Deoxyguanosine Acetylcysteine/pharmacology Animals Apoptosis/physiology Blotting, Northern Blotting, Western Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p21/metabolism DNA Damage DNA Primers Deoxyguanosine/analogs & derivatives,metabolism Gene Expression Regulation/physiology Genetic Vectors Genomic Instability/drug effects Humans Karyotyping Lentivirus Mice Models, Biological Mutagenesis RNA, Small Interfering/genetics Reactive Oxygen Species/metabolism Reverse Transcriptase Polymerase Chain Reaction Spleen/metabolism Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
Cyclin-Dependent Kinase Inhibitor p21 DNA Primers RNA, Small Interfering Reactive Oxygen Species Tumor Suppressor Protein p53 8-Hydroxy-2'-Deoxyguanosine Deoxyguanosine Acetylcysteine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Sablina Anna A
Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Budanov Andrei V
Ilyinskaya Galina V
Agapova Larissa S
Kravchenko Julia E
Chumakov Peter M
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1078-8956
DOI
10.1038/nm1320
Published
2005-12-00
Epub
2005-00-13
Pages
1306-13
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC2637821
Subset
IM
Grants
NIA NIH HHS · R01 AG025278 · United States
NIA NIH HHS · R01 AG025278-01A1 · United States
NCI NIH HHS · R01 CA104903 · United States
NCI NIH HHS · R01 CA104903-02 · United States
NCI NIH HHS · R01 CA10490 · United States
Corrections
CommentIn
PMID: 16333263
External Links
PubMed source DOI: 10.1038/nm1320 PMC Full Text View journal details
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