The Frizzled-related sFRP2 Gene Is a Target of Thyroid Hormone Receptor α1 and Activates β-Catenin Signaling in Mouse Intestine
The Frizzled-related sFRP2 Gene Is a Target of Thyroid Hormone Receptor α1 and Activates β-Catenin Signaling in Mouse Intestine
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DOI：
10.1074/jbc.m806548200
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发表时间：
2009-01-09
影响因子：
4.8
通讯作者：
Plateroti, Michelina
中科院分区：
文献类型：
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作者：
Kress, Elsa;Rezza, Amelie;Plateroti, Michelina
甲状腺激素受体TR α 1通过控制隐窝上皮细胞的增殖来调节肠道发育和体内平衡。这涉及Wnt/ β -连环蛋白途径的阳性控制。为了进一步研究甲状腺激素-TR α 1信号对肠上皮增殖室的影响，我们对激素正常或紊乱的野生型动物以及TR敲除小鼠的激光微解剖隐窝细胞进行了比较转录谱分析。统计分析和计算机方法使我们能够识别179个差异调节基因，并将它们归类为有组织的功能网络。我们专注于“细胞周期/细胞增殖”网络，特别是frizzled相关蛋白sFRP2，其表达在甲状腺激素的反应中大大增加。体外和体内分析表明，sFRP2的表达受TR α 1的直接调控，并通过卷曲受体激活β -catenin信号。事实上，sFRP2稳定β -连环蛋白，激活其靶基因，并增强细胞增殖。总之，这些新数据与我们之前的结果相结合，表明TR α 1与Wnt/ β -catenin通路组分之间存在复杂的相互作用。此外，我们在本研究中描述了负责激活β -连环蛋白信号的sFRP2的一种新的作用机制。
The thyroid hormone receptor TR alpha 1 regulates intestinal development and homeostasis by controlling epithelial proliferation in the crypts. This involves positive control of the Wnt/beta-catenin pathway. To further investigate the effect of thyroid hormone-TR alpha 1 signaling on the intestinal epithelium proliferating compartment, we performed a comparative transcription profile analysis on laser microdissected crypt cells recovered from wild type animals with normal or perturbed hormonal status, as well as from TR knock-out mice. Statistical analysis and an in silico approach allowed us to identify 179 differentially regulated genes and to group them into organized functional networks. We focused on the "cell cycle/cell proliferation" network and, in particular, on the Frizzled-related protein sFRP2, whose expression was greatly increased in response to thyroid hormones. In vitro and in vivo analyses showed that the expression of sFRP2 is directly regulated by TR alpha 1 and that it activates beta-catenin signaling via Frizzled receptors. Indeed, sFRP2 stabilizes beta-catenin, activates its target genes, and enhances cell proliferation. In conclusion, these new data, in conjunction with our previous results, indicate a complex interplay between TR alpha 1 and components of the Wnt/beta-catenin pathway. Moreover, we describe in this study a novel mechanism of action of sFRP2, responsible for the activation of beta-catenin signaling.