TY - JOUR
T1 - Reciprocal inhibition of p53 and nuclear factor-κB transcriptional activities determines cell survival or death in neurons
AU - Culmsee, Carsten
AU - Siewe, Jan
AU - Junker, Vera
AU - Retiounskaia, Marina
AU - Schwarz, Stephanie
AU - Camandola, Simonetta
AU - El-Metainy, Shahira
AU - Behnke, Hagen
AU - Mattson, Mark P.
AU - Krieglstein, Josef
PY - 2003/9/17
Y1 - 2003/9/17
N2 - 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-κB (NF-κB) in p53-mediated apoptosis, depending on the cell type and experimental conditions. Therefore, we sought to elucidate the role of NF-κB in p53-mediated neuron death. In cultured neurons DNA damaging compounds induced activation of p53, whereas NF-κB activity declined significantly. The p53 inhibitor pifithrin-α (PFT) preserved NF-κB 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-κB was reduced. In contrast, PFT blocked the interaction of p53 with the cofactor, whereas NF-κB 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-κB 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-κB with the transcriptional cofactor p300 exists in neurons. Exposure of neurons to lethal stress activates p53 and disrupts NF-κB binding to p300, thereby blocking NF-κB-mediated survival signaling. Inhibitors of p53 provide pronounced neuroprotective effects because they block p53-mediated induction of cell death and concomitantly enhance NF-κB-induced survival signaling.
AB - 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-κB (NF-κB) in p53-mediated apoptosis, depending on the cell type and experimental conditions. Therefore, we sought to elucidate the role of NF-κB in p53-mediated neuron death. In cultured neurons DNA damaging compounds induced activation of p53, whereas NF-κB activity declined significantly. The p53 inhibitor pifithrin-α (PFT) preserved NF-κB 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-κB was reduced. In contrast, PFT blocked the interaction of p53 with the cofactor, whereas NF-κB 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-κB 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-κB with the transcriptional cofactor p300 exists in neurons. Exposure of neurons to lethal stress activates p53 and disrupts NF-κB binding to p300, thereby blocking NF-κB-mediated survival signaling. Inhibitors of p53 provide pronounced neuroprotective effects because they block p53-mediated induction of cell death and concomitantly enhance NF-κB-induced survival signaling.
KW - Apoptosis
KW - Cerebral ischemia
KW - DNA damage
KW - Hippocampal cultures
KW - p300
KW - Pifithrin
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UR - http://www.scopus.com/inward/citedby.url?scp=0141569519&partnerID=8YFLogxK
M3 - Article
C2 - 13679428
AN - SCOPUS:0141569519
SN - 0270-6474
VL - 23
SP - 8586
EP - 8595
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 24
ER -