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
Laboratories of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):143-8. doi: 10.1073/pnas.0237083100. Epub 2002 Dec 23.
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.
自由基诱导的细胞应激在慢性炎症过程中促进癌症发生。在此，我们研究了自由基一氧化氮（NO）激活p53的机制。供体药物产生的NO诱导了共济失调毛细血管扩张症突变基因（ATM）和共济失调毛细血管扩张症突变基因及Rad3相关蛋白（ATR）依赖性的p53翻译后修饰，导致p53转录靶点增加和G2/M细胞周期检查点出现。在与释放NO的巨噬细胞共培养的细胞中也发现了此类修饰。在溃疡性结肠炎（一种易患癌症的慢性炎症性疾病）患者的非癌性结肠组织中，诱导型NO合酶蛋白水平与p53丝氨酸15磷酸化水平呈正相关。HDM-2和p21（WAF1）的免疫染色与转录活性p53一致。我们的研究强调了NO在慢性炎症期间诱导细胞应激和激活p53反应途径中的关键作用。
