Ectopic γ-catenin expression partially mimics the effects of stabilized β-catenin on embryonic stem cell differentiation.
Ectopic γ-catenin expression partially mimics the effects of stabilized β-catenin on embryonic stem cell differentiation.
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DOI：
10.1371/journal.pone.0065320
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Doble BW
中科院分区：
文献类型：
--
作者：
Mahendram S;Kelly KF;Paez-Parent S;Mahmood S;Polena E;Cooney AJ;Doble BW
β-catenin是一种粘附连接成分和关键的Wnt通路效应物，在特定情况下调节许多发育过程并支持胚胎干细胞（ESC）的多能性。β-catenin同源物γ-catenin（也称为血小板红蛋白）是桥粒和粘附体连接的组成部分，在某些情况下可能参与Wnt信号传导。本研究利用β-catenin（+/+）和β-catenin（−/−）小鼠胚胎干细胞（mESCs）研究γ-catenin在Wnt信号通路和mESC分化中的作用。虽然γ-catenin蛋白在野生型（WT） mESCs中抑制或消融GSK-3后显着稳定，但在这些细胞中有效沉默其表达并不影响Wnt通路刺激后β-catenin/TCF靶基因的激活。然而，在短期分化实验中，抑制γ-catenin在WT mESCs中的表达似乎促进了其多能性的退出。在β-catenin(−/−)mESCs中，GSK-3抑制不会明显改变细胞内γ-catenin水平，也不会激活TCF靶基因。有趣的是，β-catenin/TCF靶基因在β-catenin(- / -) mESCs中被诱导过表达稳定的γ-catenin，当野生型γ-catenin在这些细胞中过表达时，这些基因在GSK-3抑制下的激活能力部分恢复。这表明，必须达到总catenin表达的临界阈值水平，才能有足够的信号传导能力γ-catenin可用来响应GSK-3抑制并因此调节靶基因。稳定过表达γ-catenin的WT mESCs表现出强大的Wnt通路激活，并显示出三谱系分化的阻断，这在很大程度上模仿了β-catenin过表达时所观察到的情况。然而，β-catenin过表达似乎比γ-catenin过表达更有效地维持了在分化诱导条件下细胞中naïve多能性标记的保留。总的来说，我们的研究揭示了γ-catenin在mESC分化调控中的作用，并对γ-catenin突变和/或异常表达的人类癌症有影响。
β-catenin, an adherens junction component and key Wnt pathway effector, regulates numerous developmental processes and supports embryonic stem cell (ESC) pluripotency in specific contexts. The β-catenin homologue γ-catenin (also known as Plakoglobin) is a constituent of desmosomes and adherens junctions and may participate in Wnt signaling in certain situations. Here, we use β-catenin(+/+) and β-catenin(−/−) mouse embryonic stem cells (mESCs) to investigate the role of γ-catenin in Wnt signaling and mESC differentiation. Although γ-catenin protein is markedly stabilized upon inhibition or ablation of GSK-3 in wild-type (WT) mESCs, efficient silencing of its expression in these cells does not affect β-catenin/TCF target gene activation after Wnt pathway stimulation. Nonetheless, knocking down γ-catenin expression in WT mESCs appears to promote their exit from pluripotency in short-term differentiation assays. In β-catenin(−/−) mESCs, GSK-3 inhibition does not detectably alter cytosolic γ-catenin levels and does not activate TCF target genes. Intriguingly, β-catenin/TCF target genes are induced in β-catenin(−/−) mESCs overexpressing stabilized γ-catenin and the ability of these genes to be activated upon GSK-3 inhibition is partially restored when wild-type γ-catenin is overexpressed in these cells. This suggests that a critical threshold level of total catenin expression must be attained before there is sufficient signaling-competent γ-catenin available to respond to GSK-3 inhibition and to regulate target genes as a consequence. WT mESCs stably overexpressing γ-catenin exhibit robust Wnt pathway activation and display a block in tri-lineage differentiation that largely mimics that observed upon overexpression of β-catenin. However, β-catenin overexpression appears to be more effective than γ-catenin overexpression in sustaining the retention of markers of naïve pluripotency in cells that have been subjected to differentiation-inducing conditions. Collectively, our study reveals a function for γ-catenin in the regulation of mESC differentiation and has implications for human cancers in which γ-catenin is mutated and/or aberrantly expressed.
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DOI：
10.1083/jcb.118.3.671
发表时间：
1992-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
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通讯作者：
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DOI：
10.1242/dev.085654
发表时间：
2013-03
期刊：
Development (Cambridge, England)
影响因子：
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影响因子：
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