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首页> 外文期刊>Oncogene >Transfection of K-rasAsp12 cDNA markedly elevates IL-1|[beta]|- and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells
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Transfection of K-rasAsp12 cDNA markedly elevates IL-1|[beta]|- and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells

机译：K-rasAsp12 cDNA的转染显着提高了大鼠肠上皮细胞中IL-1 |β|-和脂多糖介导的一氧化氮合酶的表达

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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-rasAsp12 cDNA, the iNOS expression linked to interleukin-1 (IL-1) 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-rasWT. Electrophoretic mobility-shift assays demonstrated that NF-B binding activity induced by IL-1 or LPS was also increased in K-rasAsp12-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/EBP to a C/EBP-binding consensus site. Furthermore, the anchorage-independent growth of K-rasAsp12-transfected cells was markedly increased by IL-1 or LPS treatment, and decreased by ONO-1714, an iNOS inhibitor. In addition, tumor growth in nude mice injected with K-rasAsp12-transfected cells was significantly suppressed by NOS inhibition with 50p.p.m. ONO-1714 or 100p.p.m. L-NG-nitroarginine methyl ester. These results suggest that an activating mutation of K-ras can markedly enhance the iNOS expression mediated by IL-1 or LPS, through the activation of promoters on NF-B, C/EBP, and CRE-like sites, and that nitric oxide contributes to the colony formation and tumor growth of K-ras-transformed cells.
机译：K-ras的激活突变在结肠肿瘤和隐窝灶灶中很常见，并且可能在结肠癌的发生中起重要作用。在这里，我们调查了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-rasAsp12 cDNA转染大鼠肠上皮细胞（IEC-6）时，与白介素1（IL-1）或脂多糖（LPS）处理有关的iNOS表达明显增加并延长。相反，在用对照载体或K-rasWT转染的细胞中，它只是非常微弱和短暂的。电泳迁移率迁移分析表明，IL-1或LPS诱导的NF-B结合活性在K-rasAsp12转染的细胞中也增加，并且与CREB-1，CREM-1，ATF-1，ATF-2结合，和Jun D结合到cAMP响应元件（CRE）样位点，以及C / EBP与C / EBP结合共有位点的结合。此外，通过IL-1或LPS处理，K-rasAsp12转染的细胞的锚定非依赖性生长显着增加，而iNOS抑制剂ONO-1714则降低了这种生长。另外，用50p.p.m的NOS抑制显着抑制了注射K-rasAsp12转染的细胞的裸鼠的肿瘤生长。 ONO-1714或100p.p.m. L-NG-硝基精氨酸甲酯。这些结果表明，K-ras的激活突变可以通过激活NF-B，C / EBP和CRE样位点上的启动子激活，从而显着增强IL-1或LPS介导的iNOS表达，而一氧化氮有助于K-ras转化细胞的集落形成和肿瘤生长。

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