Nitric oxide (NO) is an efficient inhibitor of cell proliferation. Here we show that part of the antiproliferative activity of NO in fibroblasts is mediated through p53 signaling pathway. Cells from p53−/− knockout mice are compromised in their ability to stop dividing in the presence of NO. NO strongly induces expression of genes which are transcriptional targets of p53, and p53 is necessary for some, but not all, of the transcription activation effects of NO. Furthermore, NO strongly increases the cellular level of p53 protein. Since phosphorylation of particular residues of the p53 molecule has been correlated with its functional activity, we determined the phosphorylation pattern of p53 molecule after exposure to NO and compared it with the phosphorylation patterns that develop upon treatment with gamma-irradiation, UV light, and adriamycin. We found that NO induces a specific signature pattern of p53 phosphorylation, distinct from the patterns evoked by other inducers. This study suggests that NO activates specific signaling pathways that may partially overlap, but that do not coincide, with signaling pathways activated by other known inducers of p53 activity.
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We thank members of the Enikolopov Laboratory for help and advice. We are grateful to Julian Banerji for his invaluable advice and critical reading of the manuscript. This work was supported by grants from the NIH, the Charles Henry Leach Foundation and the Seraph Foundation to G Enikolopov and from the Henry Wendt Fellowship Program to N Nakaya. SW Lowe is a Rita Allen Foundation Scholar.
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Nakaya, N., Lowe, S., Taya, Y. et al. Specific pattern of p53 phosphorylation during nitric oxide-induced cell cycle arrest. Oncogene 19, 6369–6375 (2000). https://doi.org/10.1038/sj.onc.1204100
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