Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease
Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease
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DOI：
10.1002/em.20024
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发表时间：
2004-01-01
影响因子：
2.8
通讯作者：
Harris, CC
中科院分区：
文献类型：
--
作者：
Goodman, JE;Hofseth, LJ;Harris, CC
一氧化氮（NOcircle）是在慢性炎症条件下产生的，使个体易患癌症，具有矛盾的作用。NOcircle可以激活p53，这可能导致抗癌作用，或者它可能是诱变性的，增加癌症风险。我们探讨了NOcircle在体外诱导p53活化的机制，发现NOcircle通过ATM和ATR激酶诱导p53积聚和磷酸化，特别是在ser-15，然后导致细胞周期停滞在G（2）/M。接下来，我们检测了炎症和正常人类结肠组织中这些通路中的蛋白质。诱导型一氧化氮合酶（iNOS）和p53-P-ser 15水平与炎症程度呈正相关，且相互之间呈正相关。此外，p53靶点HDM-2和p21（WAF 1）存在于溃疡性结肠炎（UC）结肠中，但在正常结肠中检测不到，与活化的p53一致。我们还发现UC患者的病变结肠组织中密码子248的CpG位点G：C->A：T转换和密码子247的C：G->T：A转换的p53突变频率高于这些病例的非病变组织或正常成人对照的结肠组织。与亚硝化应激和5-甲基胞嘧啶的脱氨基作用一致，p53突变也在散发性结肠癌组织中检测到，并且与这些组织中的iNOS活性相关。这些研究确定了UC和散发性结肠癌中NOcircle和p53之间的潜在机制联系。
Nitric oxide (NOcircle), which is generated under chronic inflammatory conditions that predispose individuals to cancer, has paradoxical effects. NOcircle can activate p53, which can result in anti-carcinogenic effects, or it can be mutagenic and increase cancer risk. We explored the mechanisms by which NOcircle induced p53 activation in vitro and found that NOcircle induced p53 accumulation and phosphorylation, particularly at ser-15, via ATM and ATR kinases, which then led to cell cycle arrest at G(2)/M. We next examined proteins in these pathways in both inflamed and normal human colon tissue. Inducible nitric oxide synthase (iNOS) levels and p53-P-ser 15 levels were positively correlated with the degree of inflammation and with each other. Additionally, the p53 targets, HDM-2 and p21 (WAF1), were present in ulcerative colitis (UC) colon, but undetectable in normal colon, consistent with activated p53. We also found higher p53 mutant frequencies of both G:C-->A:T transitions at the CpG site of codon 248 and C:G-->T:A transitions at codon 247 in lesional colon tissue from UC cases versus nonlesional tissue from these cases or colon tissue from normal adult controls. Consistent with nitrosative stress and the deamination of 5-methylcytosine, p53 mutations were also detected in sporadic colon cancer tissue and were associated with iNOS activity in these tissues. These studies identified a potential mechanistic link between NOcircle and p53 in UC and sporadic colon cancer.