首页> 外文期刊>American Journal of Physiology >Hepatocyte growth factor regulates cyclooxygenase-2 expression via beta-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells.
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Hepatocyte growth factor regulates cyclooxygenase-2 expression via beta-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells.

机译:肝细胞生长因子通过β-catenin,Akt和p42 / p44 MAPK调节人支气管上皮细胞中的环氧合酶2表达。

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Hepatocyte growth factor (HGF) is upregulated in response to lung injury and has been implicated in tissue repair through its antiapoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play a role in cell growth. Here, we report that HGF induces gene transcription of COX-2 in human bronchial epithelial cells (HBEpC). Treatment of HBEpC with HGF resulted in phosphorylation of the HGF receptor (c-Met), activation of Akt, and upregulation of COX-2 mRNA. Adenovirus-mediated gene transfer of a dominant negative (DN) Akt mutant revealed that HGF increased COX-2 mRNA in an Akt-dependent manner. COX-2 promoter analysis in luciferase reporter constructs showed that HGF regulation required the beta-catenin-responsive T cell factor-4 binding element (TBE). The HGF activation of the COX-2 gene transcription was blocked by DN mutant of beta-catenin or by inhibitors that blocked activation of Akt. Inhibition of p42/p44 MAPK pathway blocked HGF-mediated activation of beta-catenin gene transcription but not Akt activation, suggesting that p42/p44 MAPK acts in a parallel mechanism for beta-catenin activation. We also found that inhibition of COX-2 with NS-398 blocked HGF-induced growth in HBEpC. Together, the results show that the HGF increases COX-2 gene expression via an Akt-, MAPK-, and beta-catenin-dependent pathway in HBEpC.
机译:肝细胞生长因子(HGF)在对肺部损伤的反应中被上调,并通过其抗凋亡和增殖活性参与组织修复。环氧合酶-2(COX-2)是前列腺素生物合成途径中的一种可诱导酶,并且已证明其活化在细胞生长中起作用。在这里,我们报道HGF诱导人支气管上皮细胞(HBEpC)中COX-2的基因转录。用HGF处理HBEpC导致HGF受体(c-Met)磷酸化,Akt激活和COX-2 mRNA上调。腺病毒介导的显性阴性(DN)Akt突变体的基因转移表明,HGF以Akt依赖性方式增加了COX-2 mRNA的表达。荧光素酶报道基因构建物中的COX-2启动子分析表明,HGF调节需要β-catenin响应性T细胞因子4结合元件(TBE)。 β-catenin的DN突变体或阻断Akt活化的抑制剂可阻断COX-2基因转录的HGF活化。抑制p42 / p44 MAPK途径可阻断HGF介导的β-catenin基因转录激活,但不能抑制Akt激活,这表明p42 / p44 MAPK在β-catenin激活的并行机制中起作用。我们还发现,用NS-398抑制COX-2可阻止HGF诱导的HBEpC生长。在一起,结果表明HGF通过HBEpC中的Akt,MAPK和β-catenin依赖性途径增加COX-2基因的表达。

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