Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated apoptosis in rat striatum.
Nuclear factor kappaB (NF-kappaB) appears to participate in the excitotoxin-induced apoptosis of striatal medium spiny neurons. To elucidate molecular mechanisms by which this transcription factor contributes to NMDA receptor-triggered apoptotic cascades in vivo, rats were given the NMDA receptor agonist quinolinic acid (QA) by intrastriatal infusion, and the role of NF-kappaB in the induction of apoptosis-related genes and gene products was evaluated. QA administration induced time-dependent NF-kappaB nuclear translocation. The nuclear NF-kappaB protein after QA treatment was comprised mainly 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 QA-induced NF-kappaB nuclear translocation. Immunohistochemical analysis showed that c-Myc and p53 induction occurred in the excitotoxin-sensitive medium-sized striatal neurons. NF-kappaB nuclear translocation was blocked in a dose-dependent manner by the cell-permeable recombinant peptide NF-kappaB SN50, but not by the NF-kappaB SN50 control peptide. NF-kappaB SN50 significantly inhibited the QA-induced elevation in levels of c-Myc and p53 mRNA and protein. Pretreatment or posttreatment with NF-kappaB SN50, but not the control peptide, also substantially reduced the intensity of QA-induced internucleosomal DNA fragmentation. The results suggest that NF-kappaB may promote an apoptotic response in striatal medium-sized neurons to excitotoxic insult through upregulation of c-Myc and p53. This study also provides evidence indicating an unique signaling pathway from the cytoplasm to the nucleus, which regulates p53 and c-Myc levels in these neurons during apoptosis.
Qin
Z H
ZH
Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chen
R W
RW
Wang
Y
Y
Nakai
M
M
Chuang
D M
DM
Chase
T N
TN
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D053938:DNA Fragmentation; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation
D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53