Identification of a lipid peroxidation product as a potential trigger of the p53 pathway
Identification of a lipid peroxidation product as a potential trigger of the p53 pathway
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DOI：
10.1074/jbc.m509065200
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发表时间：
2006-01-13
影响因子：
4.8
通讯作者：
Uchida, K
中科院分区：
文献类型：
--
作者：
Shibata, T;Iio, K;Uchida, K
肿瘤抑制因子和转录因子p53是细胞应激反应的关键调节因子，并且p53的激活可以触发包括神经元在内的许多细胞类型的凋亡。我们发现，这种核蛋白显着磷酸化时，人神经母细胞瘤SH-SY 5 Y细胞暴露于体外氧化多不饱和脂肪酸。为了鉴定诱导p53磷酸化的氧化脂质，我们在人神经母细胞瘤SH-SY 5 Y细胞中进行了脂质过氧化产物的筛选，并鉴定了4-氧代-2-壬烯醛（ONE），一种最近鉴定的源自ω 6多不饱和脂肪酸过氧化的醛，作为p53磷酸化的潜在诱导剂。我们还发现ONE诱导了共济失调毛细血管扩张症突变体的磷酸化，这在通过磷酸化p53传递DNA损伤信号中起着重要作用。此外，细胞暴露于ONE导致泛素化蛋白的积累和蛋白酶体活性的显着抑制，表明ONE作用于泛素-蛋白酶体途径，p53营业额的调节机制。此外，观察到ONE诱导的p53应答与细胞凋亡的诱导相关，这表明ONE通过激活p53信号通路和下调p53转换来激活p53依赖性细胞凋亡机制。最后，我们观察到ONE-2 '-脱氧鸟苷加合物，7-（2-氧代-庚基）-取代的1，N-2-乙烯基-2'-脱氧鸟苷，在散发性肌萎缩侧索硬化症患者的脊髓运动神经元中积累。这些数据可能表明ONE在氧化过程中诱导神经元凋亡程序中的潜在关键作用。
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,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.