Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines.
Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines.
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DOI：
10.1371/journal.pone.0007872
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发表时间：
2009-11-17
期刊：
影响因子：
3.7
通讯作者：
Byers SW
中科院分区：
文献类型：
--
作者：
Beildeck ME;Islam M;Shah S;Welsh J;Byers SW
维生素D受体（VDR）通路在预防和潜在治疗许多癌症中很重要。VDR作用的一个重要机制与其与Wnt/β-连环蛋白途径的相互作用有关。激动剂结合的VDR通过直接与β-连环蛋白相互作用抑制致癌Wnt/β-连环蛋白/TCF途径，并且在一些细胞中通过增加钙粘蛋白表达抑制致癌Wnt/β-连环蛋白/TCF途径，钙粘蛋白表达反过来将β-连环蛋白募集到细胞膜。在这里，我们确定TCF-4，转录调节因子和β-连环蛋白结合伴侣作为VDR途径的间接靶点。在这项工作中，我们表明，TCF-4（基因名称TCF 7 L2）是减少在乳腺的VDR敲除小鼠相比，野生型小鼠。此外，我们发现1，25（OH）2D 3在几种人结直肠癌细胞系中在RNA和蛋白水平上增加TCF-4，其作用完全依赖于VDR。人和小鼠TCF 7 L2启动子的计算机分析鉴定了几个推定的VDR结合元件。尽管TCF 7 L2启动子报告基因对外源性VDR和1，25（OH）2D 3有反应，但突变分析和染色质免疫沉淀试验表明，TCF 7 L2的增加不需要将VDR募集到已鉴定的元件上，这表明VDR的调节是间接的。这种上调需要从头蛋白合成进一步证实了这一点。虽然通常认为β-连环蛋白与TCF/LEF家族成员的结合是促癌的，但最近的研究表明TCF-4作为限制乳腺癌和结肠直肠癌细胞生长的转录抑制因子发挥作用。因此，我们得出结论，1，25（OH）2D 3/VDR介导的TCF-4增加可能在结肠癌以及糖尿病和克罗恩病中具有保护作用。
The vitamin D receptor (VDR) pathway is important in the prevention and potentially in the treatment of many cancers. One important mechanism of VDR action is related to its interaction with the Wnt/β-catenin pathway. Agonist-bound VDR inhibits the oncogenic Wnt/β-catenin/TCF pathway by interacting directly with β-catenin and in some cells by increasing cadherin expression which, in turn, recruits β-catenin to the membrane. Here we identify TCF-4, a transcriptional regulator and β-catenin binding partner as an indirect target of the VDR pathway. In this work, we show that TCF-4 (gene name TCF7L2) is decreased in the mammary gland of the VDR knockout mouse as compared to the wild-type mouse. Furthermore, we show 1,25(OH)2D3 increases TCF-4 at the RNA and protein levels in several human colorectal cancer cell lines, the effect of which is completely dependent on the VDR. In silico analysis of the human and mouse TCF7L2 promoters identified several putative VDR binding elements. Although TCF7L2 promoter reporters responded to exogenous VDR, and 1,25(OH)2D3, mutation analysis and chromatin immunoprecipitation assays, showed that the increase in TCF7L2 did not require recruitment of the VDR to the identified elements and indicates that the regulation by VDR is indirect. This is further confirmed by the requirement of de novo protein synthesis for this up-regulation. Although it is generally assumed that binding of β-catenin to members of the TCF/LEF family is cancer-promoting, recent studies have indicated that TCF-4 functions instead as a transcriptional repressor that restricts breast and colorectal cancer cell growth. Consequently, we conclude that the 1,25(OH)2D3/VDR-mediated increase in TCF-4 may have a protective role in colon cancer as well as diabetes and Crohn's disease.
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影响因子：
4.8
作者：
Amir, AL;Barua, M;Balk, SP
通讯作者：
Balk, SP
影响因子：
4.8
作者：
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通讯作者：
NORMAN, AW
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作者：
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影响因子：
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作者：
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通讯作者：
BRASITUS, TA
DOI：
10.1006/bbrc.1998.8884
发表时间：
1998-06-29
影响因子：
3.1
作者：
Alonso, M;Segura, C;Perez-Fernandez, R
通讯作者：
Perez-Fernandez, R