The balance of TCF7L2 variants with differential activities in Wnt-signaling is regulated by lithium in a GSK3beta-independent manner.
The balance of TCF7L2 variants with differential activities in Wnt-signaling is regulated by lithium in a GSK3beta-independent manner.
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DOI：
10.1016/j.bbrc.2010.07.062
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发表时间：
2010-08-20
影响因子：
3.1
通讯作者：
Mao, Catherine D.
中科院分区：
文献类型：
--
作者：
Struewing, Ian;Boyechko, Tania;Barnett, Corey;Beildeck, Marcy;Byers, Stephen W.;Mao, Catherine D.
TCF7L2转录因子是典型的Wnt/β-catenin信号的下游效应因子，它控制细胞的命运和动态平衡。然而，TCF7L2表达的复杂性以及编码具有不同N-末端和C-末端的蛋白质的大量mRNA异构体使得TCF7L2的功能和调控具有多样性。在这里，我们表明，尽管TCF7L2mRNA亚型区分胎儿、永生化和成人分化的内皮细胞(EC)，但它们不能解释ECs中缺乏显著的β-连环蛋白/TCF7活性。锂是一种Wnt信号激活剂，它增加了TCF7L2的mRNA水平，并诱导了一种RNA异构体开关，有利于缺乏C末端结构域的TCF7L2短型的表达。尽管后者存在于不同的细胞类型中，但其程度取决于TCF7L2转录的整体增加，而TCF7L2转录的增加与细胞对Wnt/β-catenin信号的反应有关。虽然GSK3RNA下调增加了TCF7L2的表达，但TCF7L2mRNA亚型并没有伴随的变化，这表明锂通过依赖GSK3RNA上调和GSK3RNA剪接非依赖于GSK3RNA对β剪接的调节而对TCF7L2的表达产生双重影响。TCF7L2E-Long形式对TCF7L2-启动子报告具有抑制活性，锂诱导内源性TCF7L2形式与天然TCF7L2-启动子染色质结合在Tcf7远端两个新的结合部位。综上所述，我们的数据揭示了锂诱导的RNA开关有利于TCF7L2-短型的表达，这导致了受TCF7L2-长型(如TCF7L2)负调控的锂靶基因的转录抑制，从而在反应细胞中放大了Wnt信号。
TCF7L2 transcription factor is a downstream effector of the canonical Wnt/β-catenin signaling, which controls cell fate and homeostasis. However, the complexity of TCF7L2 expression with numerous mRNA isoforms coding for proteins with distinct N- and C-termini allows variability in TCF7L2 functions and regulations. Here, we show that although TCF7L2 mRNA isoforms distinguish fetal, immortalized and adult differentiated endothelial cells (EC), they cannot explain the lack of significant β-catenin/TCF7 activities in ECs. Lithium, a Wnt-signaling activator, increases TCF7L2 mRNA levels and induces an RNA isoform switch favoring the expression of TCF7L2-short forms lacking the C-termini domains. Although the latter occurs in different cell types, its extent depends on the overall increase of TCF7L2 transcription, which correlates with cell-responsiveness to Wnt/β-catenin signaling. While GSK3β down-regulation increases TCF7L2 expression, there is no concomitant change in TCF7L2 mRNA isoforms, which demonstrate the dual effects of lithium on TCF7L2 expression via a GSK3β-dependent up-regulation and a GSK3β-independent modulation of RNA-splicing. TCF7L2E-long forms display a repressor activity on TCF7L2-promoter reporters and lithium induces a decrease of the endogenous TCF7L2 forms bound to native TCF7L2-promoter chromatin at two novel distal TCF7-binding sites. Altogether our data reveal a lithium-induced RNA switch favoring the expression of TCF7L2-short forms, which results in a transcriptional de-repression of lithium-target genes negatively regulated by TCF7L2-long forms, like TCF7L2, and thus to an amplification of Wnt-signaling in responsive cells.
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