Cross talk between the insulin and Wnt signaling pathways: Evidence from intestinal endocrine L cells
Cross talk between the insulin and Wnt signaling pathways: Evidence from intestinal endocrine L cells
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DOI：
10.1210/en.2007-1142
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发表时间：
2008-05-01
期刊：
影响因子：
4.8
通讯作者：
Jin, Tianru
中科院分区：
文献类型：
--
作者：
Yi, Fenghua;Sun, Jane;Jin, Tianru
胰高血糖素原基因（glu）编码肠促胰岛素激素胰高血糖素样肽-1（GLP-1），在肠内分泌L细胞中产生。我们以前发现，双向转录因子β-连环蛋白/T细胞因子（cat/TCF），经典Wnt信号通路的主要效应子，激活肠道glu表达和GLP-1产生。我们在这里表明，100 nM胰岛素刺激Glu的表达和增强GLP-1的内容在肠道GLUTag L细胞系以及在原代胎鼠肠细胞培养。在高胰岛素血症MKR小鼠体内也观察到肠glu mRNA表达和GLP-1含量增加。在GLUTag细胞中，胰岛素诱导的Glu表达激活通过介导cat/TCF激活的相同TCF位点发生。磷脂酰肌醇3-激酶抑制，而不是蛋白激酶B抑制，减弱胰岛素的刺激。此外，肠L细胞中的细胞核β-连环蛋白含量增加胰岛素。最后，胰岛素增强TCF-4和β-连环蛋白与Glu启动子G2增强子元件中的TCF位点的结合，如通过定量染色质免疫沉淀测定所确定的。总的来说，这些发现表明β-连环蛋白核转位和cat/TCF结合的增强是肠内分泌L细胞中胰岛素和Wnt信号通路之间串扰的潜在机制之一。
The proglucagon gene (glu) encodes the incretin hormone glucagon-like peptide-1 (GLP-1), produced in the intestinal endocrine L cells. We found previously that the bipartite transcription factor beta-catenin/T cell factor (cat/TCF), the major effector of the canonical Wnt signaling pathway, activates intestinal glu expression and GLP-1 production. We show here that 100 nM insulin stimulated glu expression and enhanced GLP-1 content in the intestinal GLUTag L cell line as well as in primary fetal rat intestinal cell cultures. Increased intestinal glu mRNA expression and GLP-1 content were also observed in vivo in hyperinsulinemic MKR mice. In the GLUTag cells, insulin-induced activation of glu expression occurred through the same TCF site that mediates cat/TCF activation. Phosphatidylinositol 3-kinase inhibition, but not protein kinase B inhibition, attenuated the stimulation by insulin. Furthermore, nuclear beta-catenin content in the intestinal L cells was increased by insulin. Finally, insulin enhanced the binding of TCF-4 and beta-catenin to the TCF site in the glu promoter G2 enhancer element, as determined by quantitative chromatin immunoprecipitation assay. Collectively, these findings indicate that enhancement of beta-catenin nuclear translocation and cat/TCF binding are among the mechanisms underlying cross talk between the insulin and Wnt signaling pathways in intestinal endocrine L cells.