Caudal homeobox protein Cdx-2 cooperates with Wnt pathway to regulate claudin-1 expression in colon cancer cells.
Caudal homeobox protein Cdx-2 cooperates with Wnt pathway to regulate claudin-1 expression in colon cancer cells.
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DOI：
10.1371/journal.pone.0037174
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Dhawan P
中科院分区：
文献类型：
--
作者：
Bhat AA;Sharma A;Pope J;Krishnan M;Washington MK;Singh AB;Dhawan P
紧密连接(TJ)的调节失调通常与人类疾病有关，包括癌症的发生，最近的研究支持TJ整合蛋白在调节上皮向间充质转化(EMT)中的作用。在这一点上，TJs的关键成分claudin-1在结肠癌中的表达显著增加，并与肿瘤的生长和发展密切相关。然而，对肠上皮细胞Claudin-1表达的调控机制/S仍知之甚少。在我们的研究中，我们已经在claudin-1基因的5‘侧翼区确定了肠道转录因子CDx1、-2和GATA4的可能结合部位。我们利用两个不同的人结肠癌细胞系SW480和HCT116的全长和/或缺失突变结构的进一步研究表明，CDX1、CDX2和GATA4在调节claudin-1mRNA的表达中起着关键作用。然而，过表达CDX2对claudin-1mRNA的表达和启动子活性的影响最大。此外，在结肠癌患者样本中，我们观察到claudin-1和cdx2的表达之间存在显著且平行的相关性。染色质免疫沉淀(ChIP)实验证实CDX2在体内与claudin-1启动子结合。利用CDX2缺失突变构建物，我们进一步定位了CDX2 C末端结构域在调节claudin-1启动子活性中的重要作用。有趣的是，激活的β-连环蛋白的共表达进一步诱导了依赖于CDX2的Claudin-1启动子活性的上调，而显性负性(DN)-tcf-4的表达则抑制了这种激活。综上所述，我们得出结论，同源结构域转录因子CDX1、CDX2和GATA4调控人结肠癌细胞中claudin-1基因的表达。此外，在调节claudin-1启动子的激活过程中，Wnt信号与与尾部相关的同源框(CDX)蛋白和GATA-蛋白相关的转录激活之间存在着功能上的串扰。
Dysregulation of tight junctions (TJs) is often associated with human diseases including carcinogenesis and recent studies support role of TJ integral proteins in the regulation of Epithelial-to-Mesenchymal Transition (EMT). In this regard, expression of claudin-1, a key constituent of TJs, is highly increased in colon cancer and is causally associated with the tumor growth and progression. However, mechanism/s underlying regulation of claudin-1 expression in intestinal epithelial cells remains poorly understood. In our studies, we have identified putative binding sites for intestinal transcription factors Cdx1, -2 and GATA4 in the 5′-flanking region of the claudin-1 gene. Our further studies using full length and/or deletion mutant constructs in two different human colon cancer cell lines, SW480 and HCT116, showed key role of Cdx1, Cdx2 and GATA4 in the regulation of claudin-1 mRNA expression. However, overexpression of Cdx2 had the most potent effect upon claudin-1 mRNA expression and promoter activity. Also, in colon cancer patient samples, we observed a significant and parallel correlation between claudin-1 and Cdx2 expressions. Chromatin immunoprecipitation (ChIP) assay confirmed the Cdx2 binding with claudin-1 promoter in vivo. Using Cdx2 deletion mutant constructs, we further mapped the Cdx2 C-terminus domain to be important in the regulation of claudin-1 promoter activity. Interestingly, co-expression of activated β-catenin further induced the Cdx2-dependent upregulation of claudin-1 promoter activity while expression of the dominant negative (dn)-TCF-4 abrogated this activation. Taken together, we conclude that homeodomain transcription factors Cdx1, Cdx2 and GATA4 regulate claudin-1 gene expression in human colon cancer cells. Moreover, a functional crosstalk between Wnt-signaling and transcriptional activation related to caudal-related homeobox (Cdx) proteins and GATA-proteins is demonstrated in the regulation of claudin-1 promoter-activation.
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影响因子：
30.8
作者：
Aoki, K;Tamai, Y;Taketo, MM
通讯作者：
Taketo, MM
单个基因产物Claudin -1或-2，在成纤维细胞中重构紧密结合的连接链和新兵。
影响因子：
7.8
作者：
Furuse, M;Sasaki, H;Fujimoto, K;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
4.8
作者：
Lynch, J;Suh, ER;Traber, PG
通讯作者：
Traber, PG
DOI：
10.1111/j.1432-1033.1996.t01-1-00670.x
发表时间：
1996-03-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Drummond, F;Sowden, J;Edwards, YH
通讯作者：
Edwards, YH
影响因子：
5.6
作者：
Escaffit, F;Boudreau, F;Beaulieu, JF
通讯作者：
Beaulieu, JF