The VTI1A-TCF4 colon cancer fusion protein is a dominant negative regulator of Wnt signaling and is transcriptionally regulated by intestinal homeodomain factor CDX2.
The VTI1A-TCF4 colon cancer fusion protein is a dominant negative regulator of Wnt signaling and is transcriptionally regulated by intestinal homeodomain factor CDX2.
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DOI：
10.1371/journal.pone.0200215
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Troelsen JT
中科院分区：
文献类型：
--
作者：
Davidsen J;Larsen S;Coskun M;Gögenur I;Dahlgaard K;Bennett EP;Troelsen JT
原发性结直肠肿瘤的测序已经在大约3%的结直肠癌患者中鉴定出VTI 1A和TCF 7 L2基因的基因融合，其编码含有截短的TCF 4的VTI 1A-TCF 4融合蛋白。由于Wnt信号通路的失调与结直肠癌的发展和进展相关，VTI 1A-TCF 4融合蛋白的功能特性和转录调控也可能在这些过程中发挥作用。在NCI-H508和LS 174 T结肠癌细胞系中分析VTI 1A-TCF 4融合蛋白在Wnt信号传导中的功能特征。含有VTI 1A-TCF 7 L2融合基因的NCI-H508细胞系显示无活性Wnt信号传导，并且在LS 174 T细胞中过表达VTI 1A-TCF 4融合蛋白沿着Wnt信号传导荧光素酶报告质粒显示活性抑制。在LS 174 T细胞中研究VTI 1A-TCF 4融合基因的转录调节，其中比较VTI 1A启动子与TCF 7 L2启动子的活性，并且使用结肠癌细胞系作为模型，通过荧光素酶报告基因测定分析转录因子CDX 2的VTI 1A启动子的基因调节活性。LS 174 T细胞的转染显示，VTI 1A启动子与TCF 7 L2启动子相比是高度活性的，并且CDX 2激活VTI 1A的转录。这些结果表明，VTI 1A-TCF 4融合蛋白是Wnt信号通路的显性负调控因子，并且VTI 1A的转录被CDX 2激活。
Sequencing of primary colorectal tumors has identified a gene fusion in approximately 3% of colorectal cancer patients of the VTI1A and TCF7L2 genes, encoding a VTI1A-TCF4 fusion protein containing a truncated TCF4. As dysregulation of the Wnt signaling pathway is associated with colorectal cancer development and progression, the functional properties and transcriptional regulation of the VTI1A-TCF4 fusion protein may also play a role in these processes. Functional characteristics of the VTI1A-TCF4 fusion protein in Wnt signaling were analyzed in NCI-H508 and LS174T colon cancer cell lines. The NCI-H508 cell line, containing the VTI1A-TCF7L2 fusion gene, showed no active Wnt signaling, and overexpression of the VTI1A-TCF4 fusion protein in LS174T cells along with a Wnt signaling luciferase reporter plasmid showed inhibition of activity. The transcriptional regulation of the VTI1A-TCF4 fusion gene was investigated in LS174T cells where the activity of the VTI1A promoter was compared to that of the TCF7L2 promoter, and the transcription factor CDX2 was analyzed for gene regulatory activity of the VTI1A promoter through luciferase reporter gene assay using colon cancer cell lines as a model. Transfection of LS174T cells showed that the VTI1A promoter is highly active compared to the TCF7L2 promoter, and that CDX2 activates transcription of VTI1A. These results suggest that the VTI1A-TCF4 fusion protein is a dominant negative regulator of the Wnt signaling pathway, and that transcription of VTI1A is activated by CDX2.
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Mathelier A;Fornes O;Arenillas DJ;Chen CY;Denay G;Lee J;Shi W;Shyr C;Tan G;Worsley-Hunt R;Zhang AW;Parcy F;Lenhard B;Sandelin A;Wasserman WW
通讯作者：
Wasserman WW
影响因子：
0.9
作者：
Erdfelder F;Hertweck M;Filipovich A;Uhrmacher S;Kreuzer KA
通讯作者：
Kreuzer KA
影响因子：
254.7
作者：
Torre, Lindsey A.;Bray, Freddie;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin
影响因子：
4.6
作者：
Stegmann, Anders;Hansen, Morten;Olsen, Jorgen
通讯作者：
Olsen, Jorgen