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

Carsten Culmsee, Jan Siewe, Vera Junker, Marina Retiounskaia, Stephanie Schwarz, Simonetta Camandola, Shahira El-Metainy, Hagen Behnke, Mark P. Mattson, Josef Krieglstein

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8586-8595
Number of pages10
JournalJournal of Neuroscience
Volume23
Issue number24
StatePublished - Sep 17 2003
Externally publishedYes

Keywords

  • Apoptosis
  • Cerebral ischemia
  • DNA damage
  • Hippocampal cultures
  • p300
  • Pifithrin

ASJC Scopus subject areas

  • Neuroscience(all)

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