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J. Biol. Chem. 281 (2): 1196-1204

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Identification of a Lipid Peroxidation Product as a Potential Trigger of the p53 Pathway*


Takahiro Shibata{ddagger}, Kumiko Iio{ddagger}, Yoshichika Kawai§, Noriyuki Shibata¶, Motoko Kawaguchi||, Sono Toi**, Makio Kobayashi¶, Masahiko Kobayashi{ddagger}{ddagger}, Kenichi Yamamoto{ddagger}{ddagger}, , and Koji Uchida{ddagger}1

{ddagger}Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, §Graduate School of Nutrition and Biosciences, the University of Tokushima, Tokushima 770-8503, the Departments of Pathology, ||Surgical Pathology, and **Neurology, Neurological Institute, Tokyo Women's Medical University, Tokyo 162-8666, and {ddagger}{ddagger}Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan

Abstract: The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 can trigger apoptosis in many cell types, including neurons. We found that this nuclear protein was significantly phosphorylated when human neuroblastoma SH-SY5Y cells were exposed to in vitro oxidized polyunsaturated fatty acids. To identify an oxidized lipid that induces p53 phosphorylation, we conducted a screening of lipid peroxidation products in human neuroblastoma SH-SY5Y cells and identified 4-oxo-2-nonenal (ONE), a recently identified aldehyde originating from the peroxidation of {omega}6 polyunsaturated fatty acids, as a potential inducer of the p53 phosphorylation. We also found that ONE induced the phosphorylation of ataxia telangiectasia-mutated, which plays an essential role in transmitting DNA damage signals by the phosphorylation of p53. In addition, exposure of the cells to ONE resulted in an accumulation of ubiquitinated proteins and in a significant inhibition of proteasome activities, suggesting that ONE acted on the ubiquitin-proteasome pathway, a regulatory mechanism of p53 turnover. In addition, the observation that the ONE-induced p53 response was associated with the induction of apoptosis suggested that ONE activated the p53-dependent apoptosis mechanism via activation of the p53 signaling pathway and down-regulation of the p53 turnover. Finally, we observed that the ONE-2'-deoxyguanosine adduct, 7-(2-oxo-heptyl)-substituted 1,N2-etheno-2'-deoxyguanosine, was accumulated in the spinal cord motor neurons of patients with sporadic amyotrophic lateral sclerosis. These data may suggest the potential critical role for ONE in the induction of a neuronal apoptosis program during oxidative processes.

Received for publication August 17, 2005. Revision received October 24, 2005.

* This work was supported by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology and by the COE Program in the 21st Century in Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


The on-line version of this article (available at contains Figs. S1 and S2.

1 To whom correspondence should be addressed: Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan. Tel.: 81-52-789-4127; Fax: 81-52-789-5741; E-mail: uchidak{at}

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