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The Journal of Neuroscience, March 24, 2004, 24(12):2963-2973; doi:10.1523/JNEUROSCI.0155-04.2004
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Cellular/Molecular
Nuclear Factor- B Modulates the p53 Response in Neurons Exposed to DNA Damage
Hossein Aleyasin,
Sean P. Cregan,
Grace Iyirhiaro,
Michael J. O'Hare,
Steve M. Callaghan,
Ruth S. Slack, and
David S. Park
Ottawa Health Research Institute, Neurosciences, East Division, Ottawa, Ontario, Canada K1H 8M5
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- B (NF-B) is a group of transcription factors that potentially interact with these pathways. Presently, we show that NF-B is activated shortly after induction of DNA damage in a manner independent of the classic IB kinase (IKK) activation pathway, CDKs, ATM, and p53. Acute inhibition of NF-B via expression of a stable IB mutant, downregulation of the p65 NF-B subunit by RNA interference (RNAi), or pharmacological NF-B inhibitors significantly protected against DNA damage-induced neuronal death. NF-B 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-B-mediated neuronal death. Importantly, p53 expression still induces death in the presence of NF-B inhibition, indicating that p53 acts downstream of NF-B. Interestingly, neurons cultured from p65 or p50 NF-B-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-B inhibition, prolonged NF-B inhibition caused neuronal death in the absence of DNA damage. These results uniquely define a signaling paradigm by which NF-B serves both an acute p53-dependent pro-apoptotic function in the presence of DNA damage and an anti-apoptotic function in untreated normal neurons.
Key words: embryonic cortical neurons; NF-B; camptothecin; p53; DNA damage; IB; apoptosis
Received Sep 9, 2003;
revised February 7, 2004;
accepted February 7, 2004.
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