Nitric Oxide-Induced Cellular Stress and p53 Activation in Chronic Inflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-01, Vol.100 (1), p.143-148
• Main Authors: Hofseth, Lorne J., Saito, Shin'ichi, Hussain, S. Perwez, Espey, Michael G., Miranda, Katrina M., Araki, Yuzuru, Jhappan, Chamelli, Higashimoto, Yuichiro, He, Peijun, Linke, Steven P., Quezado, Martha M., Zurer, Irit, Rotter, Varda, Wink, David A., Appella, Ettore, Harris, Curtis C.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia Mutated Proteins; Biological Sciences; Breast Neoplasms; Cell Cycle; Cell Cycle Proteins; Cell Line; Cell lines; Cellular biology; Coculture Techniques; Colitis, Ulcerative - pathology; Colitis, Ulcerative - physiopathology; Comet Assay; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - metabolism; DNA Damage; DNA-Binding Proteins; Female; Free radicals; Free Radicals - metabolism; HCT116 cells; Hematocrit; Humans; Inflammation; Inflammation - genetics; Inflammation - physiopathology; Interferon-gamma - pharmacology; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - drug effects; Macrophages - physiology; Mice; Nitric oxide; Nitric Oxide - physiology; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Phosphorylation; Phosphoserine - metabolism; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - metabolism; Transcription, Genetic; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins; Ulcerative colitis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0237083100

Free radical-induced cellular stress contributes to cancer during chronic inflammation. Here, we investigated mechanisms of p53 activation by the free radical, NO. NO from donor drugs induced both ataxia-telangiectasia mutated (ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications, leading to an increase in p53 transcriptional targets and a G2/M cell cycle checkpoint. Such modifications were also identified in cells cocultured with NO-releasing macrophages. In noncancerous colon tissues from patients with ulcerative colitis (a cancer-prone chronic inflammatory disease), inducible NO synthase protein levels were positively correlated with p53 serine 15 phosphorylation levels. Immunostaining of HDM-2 and p21WAF1 was consistent with transcriptionally active p53. Our study highlights a pivotal role of NO in the induction of cellular stress and the activation of a p53 response pathway during chronic inflammation.