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Nuclear factor kappaB nuclear translocation upregulates c-Myc and p53 expression during NMDA receptor-mediated
1Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
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.
Insights
Nuclear factor kappaB (NF-kappaB) promotes excitotoxicity-induced neuron apoptosis by upregulating c-Myc and p53. Inhibiting NF-kappaB nuclear translocation reduces DNA fragmentation, suggesting a key role in neuronal cell death pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Nuclear factor kappaB (NF-kappaB) is implicated in excitotoxin-induced neuronal apoptosis.
- Understanding the role of NF-kappaB in NMDA receptor-triggered apoptosis is crucial for neuroprotection.
Purpose of the Study:
- To investigate the molecular mechanisms by which NF-kappaB contributes to NMDA receptor-mediated apoptotic cascades in vivo.
- To evaluate the role of NF-kappaB in the induction of apoptosis-related genes and proteins following excitotoxic insult.
Main Methods:
- Rats received intrastriatal infusions of quinolinic acid (QA), an NMDA receptor agonist.
- NF-kappaB nuclear translocation, c-Myc and p53 mRNA/protein levels, and DNA fragmentation were assessed.
- The effect of NF-kappaB inhibitory peptide (SN50) on QA-induced apoptosis was evaluated.
Main Results:
- QA administration induced time-dependent NF-kappaB nuclear translocation, primarily involving p65 and c-Rel subunits.
- Levels of c-Myc and p53 mRNA and protein significantly increased in striatal neurons following QA treatment.
- NF-kappaB SN50 treatment dose-dependently blocked NF-kappaB translocation and inhibited QA-induced increases in c-Myc and p53, reducing DNA fragmentation.
Conclusions:
- NF-kappaB promotes excitotoxic apoptosis in striatal neurons by upregulating c-Myc and p53.
- A unique signaling pathway regulates p53 and c-Myc levels in neurons during apoptosis.
- Inhibiting NF-kappaB activation offers a potential therapeutic strategy against excitotoxic neuronal damage.