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首页> 外文期刊>Oncogene >Transfection of K-ras(Asp12) cDNA markedly elevates IL-1beta- and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells.
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Transfection of K-ras(Asp12) cDNA markedly elevates IL-1beta- and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells.

机译：转染 K-ras（Asp12） cDNA 可显著提高大鼠肠上皮细胞中 IL-1β 和脂多糖介导的诱导型一氧化氮合酶表达。

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Activating mutations of K-ras are frequent in colon tumors and aberrant crypt foci, and may play important roles in colon carcinogenesis. Here, we investigated the effects of a K-ras codon 12 mutation on inducible nitric oxide synthase (iNOS) expression. When rat intestinal epithelial cells (IEC-6) were transfected with K-ras(Asp12) cDNA, the iNOS expression linked to interleukin-1beta (IL-1beta) or lipopolysaccharide (LPS) treatment was markedly increased and prolonged. In contrast, it was only very faint and transient in cells transfected with the control vector or K-ras(WT). Electrophoretic mobility-shift assays demonstrated that NF-kappaB binding activity induced by IL-1beta or LPS was also increased in K-ras(Asp12)-transfected cells, along with the binding of CREB-1, CREM-1, ATF-1, ATF-2, and Jun D to a cAMP-responsive element (CRE)-like site and the binding of C/EBPbeta to a C/EBP-binding consensus site. Furthermore, the anchorage-independent growth of K-ras(Asp12)-transfected cells was markedly increased by IL-1beta or LPS treatment, and decreased by ONO-1714, an iNOS inhibitor. In addition, tumor growth in nude mice injected with K-ras(Asp12)-transfected cells was significantly suppressed by NOS inhibition with 50 p.p.m. ONO-1714 or 100 p.p.m. L-N(G)-nitroarginine methyl ester. These results suggest that an activating mutation of K-ras can markedly enhance the iNOS expression mediated by IL-1beta or LPS, through the activation of promoters on NF-kappaB, C/EBP, and CRE-like sites, and that nitric oxide contributes to the colony formation and tumor growth of K-ras-transformed cells.Oncogene (2003) 22, 7667-7676. doi:10.1038/sj.onc.1207051
机译：K-ras的激活突变在结肠肿瘤和异常隐窝病灶中很常见，并且可能在结肠癌发生中发挥重要作用。在这里，我们研究了 K-ras 密码子 12 突变对诱导型一氧化氮合酶 （iNOS） 表达的影响。用K-ras（Asp12）cDNA转染大鼠肠上皮细胞（IEC-6）时，与白细胞介素-1β（IL-1β）或脂多糖（LPS）处理相关的iNOS表达显著增加和延长。相比之下，在用对照载体或 K-ras（WT） 转染的细胞中，它只是非常微弱和短暂的。电泳迁移率转移试验表明，在 K-ras（Asp12） 转染细胞中，IL-1β 或 LPS 诱导的 NF-kappaB 结合活性也增加，CREB-1、CREM-1、ATF-1、ATF-2 和 Jun D 与 cAMP 反应元件 （CRE） 样位点的结合以及 C/EBPbeta 与 C/EBP 结合的共有位点的结合也有所增加。此外，IL-1β 或 LPS 处理显著增加 K-ras（Asp12） 转染细胞的锚定非依赖性生长，而 iNOS 抑制剂 ONO-1714 则显著降低。此外，用50 p.p.m. ONO-1714或100 p.p.m. L-N（G）-硝基精氨酸甲酯抑制NOS显著抑制了注射K-ras（Asp12）转染细胞的裸鼠的肿瘤生长。这些结果表明，K-ras的激活突变可以通过激活NF-κB、C/EBP和CRE样位点上的启动子来显著增强IL-1β或LPS介导的iNOS表达，并且一氧化氮有助于K-ras转化细胞的集落形成和肿瘤生长。癌基因 （2003） 22， 7667-7676。doi：10.1038/sj.onc.1207051

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