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Factor-B Modulates the p 53 Response in Neurons Exposed to DNA Damage

Previous studies have shown that DNA damage-evoked death of primary cortical neurons occurs in a p53 and cyclin-dependent kinasedependent (CDK) manner. The manner by which these signals modulate death is unclear. Nuclear factorB (NFB) is a group of transcription factors that potentially interact with these pathways. Presently, we show that NFB is activated shortly after induction of DNA damage in a manner independent of the classic I B kinase (IKK) activation pathway, CDKs, ATM, and p53. Acute inhibition of NFB via expression of a stable I B mutant, downregulation of the p65 NFB subunit by RNA interference (RNAi), or pharmacological NFB inhibitors significantly protected against DNA damage-induced neuronal death. NFB inhibition also reduced p53 transcripts and p53 activity as measured by the p53-inducible messages, Puma and Noxa, implicating the p53 tumor suppressor in the mechanism of NFB-mediated neuronal death. Importantly, p53 expression still induces death in the presence of NFB inhibition, indicating that p53 acts downstream of NFB. Interestingly, neurons cultured from p65 or p50 NFB-deficient mice were not resistant to death and did not show diminished p53 activity, suggesting compensatory processes attributable to germline deficiencies, which allow p53 activation still to occur. In contrast to acute NFB inhibition, prolonged NFB inhibition caused neuronal death in the absence of DNA damage. These results uniquely define a signaling paradigm by which NFB serves both an acute p53-dependent pro-apoptotic function in the presence of DNA damage and an anti-apoptotic function in untreated normal neurons.