Reciprocal inhibition of p53 and nuclear factor-κB transcriptional activities determines cell survival or death in neurons

被引:0
|
作者
Culmsee, C
Siewe, J
Junker, V
Retiounskaia, M
Schwarz, S
Camandola, S
El-Metainy, S
Behnke, H
Mattson, MP
Krieglstein, J
机构
[1] Univ Munich, Zentrum Arzneimittelforsch, Dept Pharm, D-81377 Munich, Germany
[2] Univ Marburg, Inst Pharmakol, D-35037 Marburg, Germany
[3] Univ Marburg, Klin Anasthesie & Intens Therapie, D-35037 Marburg, Germany
[4] NIA, Neurosci Lab, Baltimore, MD 21224 USA
来源
JOURNAL OF NEUROSCIENCE | 2003年 / 23卷 / 24期
关键词
pifithrin; apoptosis; p300; DNA damage; cerebral ischemia; hippocampal cultures;
D O I
暂无
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 precedes apoptosis in many cell types. Controversial reports exist on the role of the transcription factor nuclear factor-kappaB (NF-kappaB) in p53-mediated apoptosis, depending on the cell type and experimental conditions. Therefore, we sought to elucidate the role of NF-kappaB in p53-mediated neuron death. In cultured neurons DNA damaging compounds induced activation of p53, whereas NF-kappaB activity declined significantly. The p53 inhibitor pifithrin-alpha (PFT) preserved NF-kappaB activity and protected neurons against apoptosis. Immunoprecipitation experiments revealed enhanced p53 binding to the transcriptional cofactor p300 after induction of DNA damage, whereas binding of p300 to NF-kappaB was reduced. In contrast, PFT blocked the interaction of p53 with the cofactor, whereas NF-kappaB binding to p300 was enhanced. Most interestingly, similar results were observed after oxygen glucose deprivation in cultured neurons and in ischemic brain tissue. Ischemia-induced repression of NF-kappaB activity was prevented and brain damage was reduced by the p53 inhibitor PFT in a dose-dependent manner. It is concluded that a balanced competitive interaction of p53 and NF-kappaB with the transcriptional cofactor p300 exists in neurons. Exposure of neurons to lethal stress activates p53 and disrupts NF-kappaB binding to p300, thereby blocking NF-kappaB-mediated survival signaling. Inhibitors of p53 provide pronounced neuroprotective effects because they block p53-mediated induction of cell death and concomitantly enhance NF-kappaB-induced survival signaling.
引用
收藏
页码:8586 / 8595
页数:10
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