Nuclear factor kappa B nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum

Nuclear factor kappa B (NF-kappa B) appears to participate in the excitotox in-induced apoptosis of striatal medium spiny neurons. To elucidate molecul ar mechanisms by which this transcription factor contributes to NMDA recept or-triggered apoptotic cascades in vivo, rats were given the NMDA receptor agonist quinolinic acid (QA) by intrastriatal infusion, and the role of NF- kappa B in the induction of apoptosis-related genes and gene products was e valuated. QA administration induced time-dependent NF-kappa B nuclear trans location. The nuclear NF-kappa B protein after QA treatment was comprised m ainly of p65 and c-Rel subunits as detected by gel supershift assay. Levels of c-Myc and p53 mRNA and protein were markedly increased at the time of Q A-induced NF-kappa B nuclear translocation. Immunohistochemical analysis sh owed that c-Myc and p53 induction occurred in the excitotoxin-sensitive med ium-sized striatal neurons. NF-kappa B nuclear translocation was blocked in a dose-dependent manner by the cell-permeable recombinant peptide NF-kappa B SN50, but not by the NF-kappa B SN50 control peptide. NF-kappa B SN50 si gnificantly inhibited the QA-induced elevation in levels of c-Myc and p53 m RNA and protein. Pretreatment or posttreatment with NF-kappa B SN50, but no t the control peptide, also substantially reduced the intensity of QA-induc ed internucleosomal DNA fragmentation. The results suggest that NF-kappa B may promote an apoptotic response in striatal medium-sized neurons to excit otoxic insult through upregulation of c-Myc and p53. This study also provid es evidence indicating an unique signaling pathway from the cytoplasm to th e nucleus, which regulates p53 and c-Myc levels in these neurons during apo ptosis.