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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 …