Human Molecular Genetics Advance Access originally published online on May 11, 2005
Human Molecular Genetics 2005 14(12):1699-1708; doi:10.1093/hmg/ddi181
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Cancer chemoprevention by the antioxidant tempol acts partially via the p53 tumor suppressor
1Department of Pediatrics, 2Department of Medicine and 3Comprehensive Cancer Center, UCSD School of Medicine, La Jolla 92093, USA, 4Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD 20892, USA and 5Radiation Biology Branch, NCI, Bethesda, MD 20892, USA
* To whom correspondence should be addressed at: San Diego School of Medicine, University of California, 9500 Gilman Drive, Mailstop 0627, La Jolla, CA 92093-0627, USA. Tel: +1 8588223400; Fax: +1 8588223409; Email: awynshawboris{at}ucsd.edu
Received March 18, 2005; Accepted May 3, 2005
We previously demonstrated that the nitroxide antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) increased latency to tumorigenesis and doubled (100%) the lifespan of Atm-deficient mice, a mouse model of ataxia telangiectasia, which displays accelerated oxidative damage and stress. Tempol treatment of cancer-prone p53-deficient mice resulted in a small but significant (25%) increase in lifespan by prolonging latency to tumorigenesis, demonstrating that existing oxidative stress and damage are not necessary for the chemopreventative effects of tempol. However, the relatively small effect on latency in p53-deficient mice and the finding that tempol-mediated resistance to oxidative insult was p53-dependent suggested a more direct role of p53 in the chemopreventative effects of tempol. Surprisingly, tempol treatment specifically increased serine 18 phosphorylation of p53 (but not 
-H2AX) and p21 expression in primary thymocytes in vitro in a p53-dependent fashion. Inhibition of phosphoinositide 3-kinase (PI3K) family members suggested that SMG-1 was responsible for the tempol-mediated enhancement of p53 serine 18 phosphorylation. These data suggest that the chemopreventative effect of tempol is not solely due to the reduction of oxidative stress and damage but may also be related to redox-mediated signaling functions that include p53 pathway activation.
Present address: Department of Pediatrics, J. W. Goethe-University, Frankfurt, Germany.
Present address: Department of Surgery, Taku Hospital, Saga, Japan.
¶ Present address: BrainCells Inc., San Diego, CA, USA.
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