Cdx1 inhibits human colon cancer cell proliferation by reducing β-catenin/T-cell factor transcriptional activity
Cdx1 inhibits human colon cancer cell proliferation by reducing β-catenin/T-cell factor transcriptional activity
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DOI：
10.1074/jbc.m405213200
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发表时间：
2004-08-27
影响因子：
4.8
通讯作者：
Lynch, JP
中科院分区：
文献类型：
--
作者：
Guo, RJ;Huang, E;Lynch, JP
增殖的停止和分化的诱导是在肠隐窝中连续发生的高度协调的过程。同源结构域转录因子Cdx 1和Cdx 2调节精氨酸特异性基因表达和肠上皮细胞分化。它们在调节增殖方面的作用已得到承认，但仍知之甚少。以前，我们证明Cdx 1表达减少了人类结肠癌细胞的增殖，部分通过减少细胞周期蛋白D1基因的表达。为了进一步阐明这一现象背后的分子机制，我们首先假设Cdx 1或Cdx 2表达通过抑制β-连环蛋白/T细胞因子（TCF）转录活性来降低结肠癌细胞增殖。我们报告说，Cdx 1或Cdx 2的表达抑制β-连环蛋白/TCF在结肠癌细胞的转录活性。这种抑制作用是剂量依赖性的，并在不同的结肠癌细胞系中观察到，抑制程度与Cdx 1减少细胞增殖的能力相关。Cdx 1表达不改变β-连环蛋白水平或细胞内分布，也不诱导抑制性TCF亚型。我们还发现，Cdx 1的表达丢失在Min小鼠息肉与增加β-连环蛋白的核定位，表明Cdx 1不支持β-连环蛋白介导的转化。最后，我们表明，结肠癌细胞有效地减少Cdx 2介导的抑制Wnt/β-连环蛋白/TCF转录活性相比，与其他模型系统。这表明结肠癌和可能的隐窝上皮细胞可以调节Cdx 2对β-连环蛋白信号传导和增殖的影响。我们的结论是Cdx 1和Cdx 2通过阻断β-连环蛋白/TCF转录活性抑制结肠癌细胞增殖。
The cessation of proliferation and the induction of differentiation are highly coordinated processes that occur continuously in the intestinal crypts. The homeodomain transcription factors Cdx1 and Cdx2 regulate intestine-specific gene expression and enterocyte differentiation. Their roles in regulating proliferation are recognized but remain poorly understood. Previously, we demonstrated that Cdx1 expression diminished the proliferation of human colon cancer cells in part by reducing cyclin D1 gene expression. In order to elucidate further the molecular mechanisms underlying this phenomenon, we first hypothesized that Cdx1 or Cdx2 expression reduces colon cancer cell proliferation by inhibiting beta-catenin/T-cell factor (TCF) transcriptional activity. We report that Cdx1 or Cdx2 expression does inhibit beta-catenin/TCF transcriptional activity in colon cancer cells. This inhibitory effect is dose-dependent and is observed in different colon cancer cell lines, and the degree of inhibition correlates with the ability of Cdx1 to reduce cell proliferation. Cdx1 expression does not alter beta-catenin protein levels or intracellular distribution nor does it induce an inhibitory TCF isoform. We also find that Cdx1 expression is lost in Min mouse polyps with increased nuclear localization of beta-catenin, suggesting that Cdx1 does not support beta-catenin-mediated transformation. Finally, we show that colon cancer cells effectively reduce Cdx2-mediated inhibition of Wnt/beta-catenin/TCF transcriptional activity when compared with other model systems. This suggests that colon cancer and possibly crypt epithelial cells can modulate the effects of Cdx2 on beta-catenin signaling and proliferation. We conclude that Cdx1 and Cdx2 inhibit colon cancer cell proliferation by blocking beta-catenin/TCF transcriptional activity.