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

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 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,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.

Technical‐grade perfluorooctane sulfonate alters the expression of more transcripts in cultured chicken embryonic hepatocytes than linear perfluorooctane sulfonate

“…Perfluorooctane sulfonate does not appear to be genotoxic [50][51][52], although Liu et al [34] did report DNA damage at high PFOS exposures but concluded that it was likely apoptosis related. Recent evidence has shown that lipid peroxidation products can activate TP53 [53], which may explain results from the present study. The fact that both Mdm2, a gene that inactivates TP53, and Cdkn2A, which modulates Mdm2 activity [54], were both overexpressed following PFOS exposure is further evidence that TP53 activity was perturbed.…”

Quantum dot-induced cell death involves Fas upregulation and lipid peroxidation in human neuroblastoma cells

“…In addition to causing membrane instability and increasing the vulnerability of the cell to subsequent insults [28], lipid peroxidation can also generate harmful and relatively stable aldehyde products which add to the oxidative stress. One of these damaging aldehydes is 4-oxo-2-nonenal (ONE), which acts by activation of the p53 signaling pathway and induces apoptosis in SH-SY5Y neuroblastoma cells [42]. …”

TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population

“…This protein has been observed in unstable atherosclerotic carotid plaque and the p53 pathway may be activated by lipid peroxidation products, as observed in human neuroblastoma cells (4). Furthermore, the involvement of p53 in some age-associated morbidities such as diabetes (5) and fatty liver diseases (6) has also been described.…”