Abstract
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 G(2)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 p21(WAF1) 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.
MeSH terms
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Animals
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Ataxia Telangiectasia / genetics
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Ataxia Telangiectasia Mutated Proteins
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Breast Neoplasms
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Cell Cycle
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Cell Cycle Proteins
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Cell Line
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Coculture Techniques
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Colitis, Ulcerative / pathology
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Colitis, Ulcerative / physiopathology*
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Comet Assay
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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DNA Damage*
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DNA-Binding Proteins
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Female
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Free Radicals / metabolism
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Humans
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Inflammation / genetics
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Inflammation / physiopathology*
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Interferon-gamma / pharmacology
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / physiology
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Mice
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Nitric Oxide / physiology*
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Phosphorylation
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Phosphoserine / metabolism
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / metabolism
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Transcription, Genetic
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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Free Radicals
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Lipopolysaccharides
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Phosphoserine
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Nitric Oxide
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Interferon-gamma
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases