Identification of a lipid peroxidation product as a potential trigger of the p53 pathway

Takahiro Shibata, Kumiko Iio, Yoshichika Kawai, Noriyuki Shibata, Motoko Kawaguchi, Sono Toi, Makio Kobayashi, Masahiko Kobayashi, Kenichi Yamamoto, Koji Uchida

Research output: Contribution to journalArticle

55 Citations (Scopus)

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 ω6 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 path-way and down-regulation of the p53 turnover. Finally, we observed that the ONE-2′-deoxyguanosine adduct, 7-(2-oxo-heptyl)-substituted 1,N 2-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.

Original languageEnglish
Pages (from-to)1196-1204
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number2
DOIs
Publication statusPublished - Jan 13 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Identification of a lipid peroxidation product as a potential trigger of the p53 pathway'. Together they form a unique fingerprint.

  • Cite this

    Shibata, T., Iio, K., Kawai, Y., Shibata, N., Kawaguchi, M., Toi, S., Kobayashi, M., Kobayashi, M., Yamamoto, K., & Uchida, K. (2006). Identification of a lipid peroxidation product as a potential trigger of the p53 pathway. Journal of Biological Chemistry, 281(2), 1196-1204. https://doi.org/10.1074/jbc.M509065200