Nitric oxide promotes p53 nuclear retention and sensitizes neuroblastoma cells to apoptosis by ionizing radiation.
Nitric oxide (NO) is a potent activator of the p53 tumor suppressor protein. However, the mechanisms underlying p53 activation by NO have not been fully elucidated. We previously reported that a rapid downregulation of Mdm2 by NO may contribute to the early phase of p53 activation. Here we show that NO promotes p53 nuclear retention and inhibits Mdm2-mediated p53 nuclear export. NO induces phosphorylation of p53 on serine 15, which does not require ATM but rather appears to depend on the ATM-related ATR kinase. An ATR-kinase dead mutant or caffeine, which blocks the kinase activity of ATR, effectively abolishes the ability of NO to cause p53 nuclear retention, concomitant with its inhibition of p53 serine 15 phosphorylation. Of note, NO enhances markedly the ability of low-dose ionizing radiation to elicit apoptotic killing of neuroblastoma cells expressing cytoplasmic wild-type p53. These findings imply that, through augmenting p53 nuclear retention, NO can sensitize tumor cells to p53-dependent apoptosis. Thus, NO donors may potentially increase the efficacy of radiotherapy for treatment of certain types of cancer.
1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
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Wang
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Zalcenstein
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D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005260:Female; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D009687:Nuclear Proteins; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D051736:Proto-Oncogene Proteins c-mdm2; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*
D018797:Cell Cycle Proteins; D020030:Nitric Oxide Donors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; C497206:MDM2 protein, human; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases