Specific pattern of p53 phosphorylation during nitric oxide-induced cell cycle arrest

Nitric oxide (NO) is an efficient inhibitor of cell proliferation. Here we show that part of the antiproliferative activity of NO in fibroblasts is me diated through p53 signaling pathway. Cells from p53-/- knockout mice are c ompromised in their ability to stop dividing in the presence of NO, NO stro ngly 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 p5 3 protein. Since phosphorylation of particular residues of the p53 molecule has been correlated with its functional activity, we determined the phosph orylation pattern of p53 molecule after exposure to NO and compared it with the phosphorylation patterns that develop upon treatment with gamma-irradi ation, UV light, and adriamycin. We found that NO induces a specific signat ure pattern of p53 phosphorylation, distinct from the patterns evoked by ot her inducers. This study suggests that NO activates specific signaling path ways that may partially overlap, but that do not coincide, with signaling p athways activated by other known inducers of p53 activity.