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The Journal of Neuroscience, May 15, 1999, 19(10):4023-4033
Nuclear Factor  B Nuclear Translocation Upregulates c-Myc and
p53 Expression during NMDA Receptor-Mediated Apoptosis in Rat
Striatum
Zheng-Hong
Qin1,
Ren-Wu
Chen2,
Yumei
Wang1,
Masami
Nakai1,
De-Maw
Chuang2, and
Thomas N.
Chase1
1 Experimental Therapeutics Branch, and
2 National Institute of Neurological Diseases and Stroke
and Section on Molecular Neurobiology, National Institute of Mental
Health, National Institutes of Health, Bethesda, Maryland 20892
Nuclear factor  B (NF-B) 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-B in the
induction of apoptosis-related genes and gene products was evaluated.
QA administration induced time-dependent NF-B nuclear translocation. The nuclear NF-B 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-B nuclear translocation. Immunohistochemical analysis
showed that c-Myc and p53 induction occurred in the
excitotoxin-sensitive medium-sized striatal neurons. NF-B nuclear
translocation was blocked in a dose-dependent manner by the
cell-permeable recombinant peptide NF-B SN50, but not by the NF-B
SN50 control peptide. NF-B SN50 significantly inhibited the
QA-induced elevation in levels of c-Myc and p53 mRNA and protein.
Pretreatment or posttreatment with NF-B SN50, but not the
control peptide, also substantially reduced the intensity of QA-induced
internucleosomal DNA fragmentation. The results suggest that NF-B
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.
Key words:
transcription factor; NF-B; quinolinic acid; tumor
suppressor gene; apoptosis; Huntington's disease
Copyright © 1999 Society for Neuroscience 0270-6474/99/19104023-11$05.00/0
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