title: Nuclear factor-(kappa)B modulates the p53 response in neurons exposed to DNA damage.
abstract: Previous studies have shown that DNA damage-evoked death of primary cortical neurons occurs in a p53 and cyclin-dependent kinase-dependent (CDK) manner. The manner by which these signals modulate death is unclear. Nuclear factor-kappaB (NF-kappaB) is a group of transcription factors that potentially interact with these pathways. Presently, we show that NF-kappaB is activated shortly after induction of DNA damage in a manner independent of the classic IkappaB kinase (IKK) activation pathway, CDKs, ATM, and p53. Acute inhibition of NF-kappaB via expression of a stable IkappaB mutant, downregulation of the p65 NF-kappaB subunit by RNA interference (RNAi), or pharmacological NF-kappaB inhibitors significantly protected against DNA damage-induced neuronal death. NF-kappaB 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 NF-kappaB-mediated neuronal death. Importantly, p53 expression still induces death in the presence of NF-kappaB inhibition, indicating that p53 acts downstream of NF-kappaB. Interestingly, neurons cultured from p65 or p50 NF-kappaB-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 NF-kappaB inhibition, prolonged NF-kappaB inhibition caused neuronal death in the absence of DNA damage. These results uniquely define a signaling paradigm by which NF-kappaB serves both an acute p53-dependent pro-apoptotic function in the presence of DNA damage and an anti-apoptotic function in untreated normal neurons.
authors.affiliation: Ottawa Health Research Institute, Neurosciences, East Division, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Hossein
authors.initials: H
authors.lastname: Aleyasin
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cregan
authors.forename: Grace
authors.initials: G
authors.lastname: Iyirhiaro
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Hare
authors.forename: Steve M
authors.initials: SM
authors.lastname: Callaghan
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606205:Nfkbia protein, mouse; D059004:Topoisomerase I Inhibitors; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D002166:Camptothecin