Quantitative analysis for transcriptional alteration of glycosyltransferases in colon cancer

结肠癌糖基转移酶转录改变的定量分析

基本信息

批准号：
13671340
负责人：
WATANABE Masahiko
金额：
$ 0.77万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671340/
关键词：
glycosyltransferase colon cancer galactosyltransferase

项目摘要

The type 1 carbohydrate chain,Gal β 1-3GlcNAc,is synthesized by UDP-galactose:β-N-acetylglucoamine β 1,3-galactosyltransferase (β 3Gal-T). Among six β 3Gal-Ts cloned to date, β 3Gal-T5 is an essential enzyme for the synthesis of type 1 chain in epithelium of digestive tracts or pancreatic tissue. It forms the type 1 structure on glycoproteins produced from such tissues. In the present study,we found that the transcriptional regulation for β 3Gal-T5 gene is controlled by homeoproteins, i.e. members of Cdx and hepatocyte nuclear factor (HNF) families. We found an important region (-151~-121 from the transcription initiation site),named the β 3Gal-T5 control element(GCE), for the promoter activity. GCE contained the consensus sequences for members of Cdx and HNF families. Mutations introduced into this sequence abolished the transcriptional activity. Four factors,Cdx1,Cdx2,HNF1 α and HNF1 β,could bind to GCE and transcriptionally activated the β 3Gal-T5 geneTranscriptional regulation of the β3Gal-T5 gene was consistent with that of the members of Cdx and HNF1 families in two in vivo systems,i.e.1) During in vitro differentiation of Caco-2 cells, transcriptional up-regulation of β 3Gal-T5 was observed in correlation with the increase in transcripts for Cdx2 and HNF1 α. 2) Both transcript and protein of β 3Gal-T5 were determined to be significantly down-regulated in cancerous tissue of colon cancer patients. This down-regulation was correlated with the decrease of Cdx1 and HNF1 β expression in cancer tissueThis is the first finding that a glycosyltransferase gene is transcriptionally regulated under control of homeoproteins in a tissue-specific manner. β 3Gal-T5,controlled by the intestinal homeoproteins, may play an important role for the specific function of intestinal cells by modifying the carbohydrate structure of glycoproteins

1 型糖链 Gal β 1-3GlcNAc 由 UDP-半乳糖：β-N-乙酰葡糖胺 β 1,3-半乳糖基转移酶（β 3Gal-T）合成。迄今为止克隆的 6 个 β 3Gal-T 中，β 3Gal-。 T5是消化道或胰腺组织上皮细胞合成1型链的必需酶。在本研究中，我们发现 β 3Gal-T5 基因的转录调控是由同源蛋白（即 Cdx 和肝细胞核因子 (HNF) 家族的成员）控制的。区域（转录起始位点-151~-121），命名为β3Gal-T5控制元件（GCE），GCE包含启动子活性的共有序列。 Cdx 和 HNF 家族成员的突变消除了四个因子，Cdx1、Cdx2、HNF1 α 和 HNF1 β，可以与 GCE 结合并转录激活 β 3Gal-T5 基因。与两个体内系统中的 Cdx 和 HNF1 家族成员一致，即 1) 在体外分化期间Caco-2 细胞中，观察到 β 3Gal-T5 的转录上调与 Cdx2 和 HNF1 α 转录物的增加相关。2) β 3Gal-T5 的转录物和蛋白质在癌性细胞中均显着下调。这种下调与癌症组织中 Cdx1 和 HNF1 β 表达的降低相关，这是糖基转移酶基因在转录调控下的首次发现。肠道同源蛋白以组织特异性方式控制同源蛋白，β3Gal-T5可能通过改变糖蛋白的碳水化合物结构对肠细胞的特定功能发挥重要作用。