ONE Triggers p53-Mediated Cell Death

Abstract

Oxidation of polyunsaturated lipids is one mechanism by which free radicals damage cells. Shibata et al. show that in vitro oxidation of polyunsaturated lipids formed the oxidized lipid ONE (4-oxo-2-nonenal) and that this lipid specifically stimulated the phosphorylation of p53 and transcriptional activation of the p53 targets, fas and gadd45 , when applied to the neuroblastoma cell line SH-SY5Y. Exposure of cells to ONE, which can form a deoxyguanosine adduct, triggered phosphorylation of the kinase ATM, which is involved in detecting DNA damage and which phosphorylates p53. In cells in which the abundance of ATM was decreased by RNA interference, ONE produced less phosphorylation of p53. Cells exposed to ONE also exhibited accumulation of ubiquitinated proteins and inhibition of the proteasome. Cells exposed to ONE also underwent apoptosis. Finally, using an antibody that specifically recognizes the ONE-2'-deoxyguanosine adduct, the abundance of this adduct was found to be increased in the atrophic motor neurons and surrounding glial cells of patients with amyotrophic lateral sclerosis (ALS). Thus, ONE may be responsible for lipid peroxidation-mediated damage that contributes to neurodegeneration in ALS. T. Shibata, K. Iio, Y. Kawai, N. Shibata, M. Kawaguchi, S. Toi, M. Kobayashi, M. Kobayashi, K. Yamamoto, K. Uchida, Identification of a lipid peroxidation product as a potential trigger of the p53 pathway. J. Biol. Chem. 281 , 1196-1204 (2006). [Abstract] [Full Text]