Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4.
Down-regulation of the Wnt/β-catenin signaling pathway by Cacnb4.
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DOI：
10.1091/mbc.e17-01-0076
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发表时间：
2017-12-01
影响因子：
3.3
通讯作者：
Ronjat M
中科院分区：
文献类型：
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作者：
Rima M;Daghsni M;Lopez A;Fajloun Z;Lefrancois L;Dunach M;Mori Y;Merle P;Brusés JL;De Waard M;Ronjat M
电压门控钙通道的细胞质 β4 亚基已被证明参与基因转录的调节。该亚基与转录因子 TCF4 相互作用并抑制 Wnt/β-catenin 信号通路。这些结果也可以解释β4亚基对细胞增殖的抑制作用。电压门控钙通道 β 亚基的 β4 亚型调节细胞增殖和细胞周期进程。在此，我们表明，在肝癌细胞系中，β4 亚基与经典 Wnt/β-catenin 信号通路的作用者共表达会抑制 Wnt 响应基因转录并减少细胞分裂，这与 Wnt 通路在细胞增殖中的作用一致。在 LiCl 存在的情况下观察到 β4 亚基介导的 Wnt 信号传导抑制，LiCl 是一种糖原合酶激酶 (GSK3) 抑制剂，可促进 β-连环蛋白易位至细胞核。失去易位至细胞核能力的β4亚基突变体的表达对Wnt信号传导没有影响，表明Wnt信号传导的β4亚基抑制发生在GSK3下游并且需要将β4亚基靶向细胞核。 β4 亚基与 TCF4 转录因子发生免疫共沉淀，TCF4 的过表达可逆转 β4 亚基对 Wnt 通路的影响。因此，我们提出核β4亚基与TCF4的相互作用阻止β-连环蛋白与TCF4结合并导致Wnt反应基因转录的抑制。因此，我们的结果表明β4-亚基是TCF4阻遏物，因此似乎是在β4-亚基特异性表达的神经元中调节该通路的有趣候选者。
The cytoplasmic β4-subunit of the voltage-gated calcium channels has been shown be involved in the regulation of gene transcription. This subunit interacts with the transcription factor TCF4 and inhibits the Wnt/β-catenin signaling pathway. These results may also explain the inhibitory effect of the β4-subunit on cell proliferation. The β4 isoform of the β-subunits of voltage-gated calcium channel regulates cell proliferation and cell cycle progression. Herein we show that coexpression of the β4-subunit with actors of the canonical Wnt/β-catenin signaling pathway in a hepatoma cell line inhibits Wnt-responsive gene transcription and decreases cell division, in agreement with the role of the Wnt pathway in cell proliferation. β4-subunit–mediated inhibition of Wnt signaling is observed in the presence of LiCl, an inhibitor of glycogen synthase kinase (GSK3) that promotes β-catenin translocation to the nucleus. Expression of β4-subunit mutants that lost the ability to translocate to the nucleus has no effect on Wnt signaling, suggesting that β4-subunit inhibition of Wnt signaling occurs downstream from GSK3 and requires targeting of β4-subunit to the nucleus. β4-subunit coimmunoprecipitates with the TCF4 transcription factor and overexpression of TCF4 reverses the effect of β4-subunit on the Wnt pathway. We thus propose that the interaction of nuclear β4-subunit with TCF4 prevents β-catenin binding to TCF4 and leads to the inhibition of the Wnt-responsive gene transcription. Thereby, our results show that β4-subunit is a TCF4 repressor and therefore appears as an interesting candidate for the regulation of this pathway in neurons where β4-subunit is specifically expressed.