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The Journal of Neuroscience, September 17, 2003, 23(24):8586-8595
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Reciprocal Inhibition of p53 and Nuclear Factor- B Transcriptional Activities Determines Cell Survival or Death in Neurons
Carsten Culmsee,1,3
Jan Siewe,1
Vera Junker,1
Marina Retiounskaia,1
Stephanie Schwarz,1
Simonetta Camandola,4
Shahira El-Metainy,2
Hagen Behnke,2
Mark P. Mattson,4 and
Josef Krieglstein1
1Institut für Pharmakologie und Toxikologie and 2Klinik für Anästhesie und Intensivtherapie, Philipps-Universität, D-35037 Marburg, Germany, 3Department Pharmazie, Ludwig-Maximilians-Universität, D-81377 München, Germany, and 4Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland 21224
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- B (NF-B) in p53-mediated apoptosis, depending on the cell type and experimental conditions. Therefore, we sought to elucidate the role of NF-B in p53-mediated neuron death. In cultured neurons DNA damaging compounds induced activation of p53, whereas NF-B activity declined significantly. The p53 inhibitor pifithrin- (PFT) preserved NF-B 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-B was reduced. In contrast, PFT blocked the interaction of p53 with the cofactor, whereas NF-B binding to p300 was enhanced. Most interestingly, similar results were observed after oxygen glucose deprivation in cultured neurons and in ischemic brain tissue. Ischemiainduced repression of NF-B 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-B with the transcriptional cofactor p300 exists in neurons. Exposure of neurons to lethal stress activates p53 and disrupts NF-B binding to p300, thereby blocking NF-B-mediated survival signaling. Inhibitors of p53 provide pronounced neuroprotective effects because they block p53-mediated induction of cell death and concomitantly enhance NF-B-induced survival signaling.
Key words: pifithrin; apoptosis; p300; DNA damage; cerebral ischemia; hippocampal cultures
Received May 27, 2003;
revised July 29, 2003;
accepted July 30, 2003.
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