SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling
SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling
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DOI：
10.1073/pnas.0911325107
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发表时间：
2010-05-18
影响因子：
11.1
通讯作者：
Pruitt, Kevin
中科院分区：
文献类型：
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作者：
Holloway, Kimberly R.;Calhoun, Tara N.;Pruitt, Kevin
Sirtuin 1 (SIRT1) 是一种 III 类组蛋白脱乙酰酶，可对组蛋白和非组蛋白进行脱乙酰化，从而调节基因转录和蛋白质功能。由于 SIRT1 调节非常多样化的反应，例如细胞凋亡、胰岛素敏感性、自噬、分化和干细胞多能性，因此协调它如何协调这种多效性效应一直是一个挑战。在这里，我们证明 SIRT1 是 Wnt 信号传导的重要调节因子。我们证明 SIRT1 功能丧失会导致所有三种 Disheveled (Dvl) 蛋白的水平显着下降。此外，我们证明 SIRT1 和 Dvl 蛋白在体内复合，并且抑制 SIRT1 会导致 Wnt 靶基因的基因表达发生变化。最后，我们证明 SIRT1 抑制剂可以抑制 Wnt 刺激的细胞迁移。由于三种哺乳动物 Dvl 蛋白充当多达 19 个 Wnt 配体的关键信使，因此 SIRT1 介导的 Dvl 蛋白调节可以解释在不同细胞环境中观察到的不同生理反应。此前，SIRT1 仅被证明可以介导 Wnt 拮抗剂的表观遗传沉默。相比之下，我们在此报告 SIRT1 在多种细胞环境中调节 Dvl 蛋白水平和 Wnt 信号传导。这些发现表明 SIRT1 是瞬时和组成性 Wnt 信号传导的调节因子。
Sirtuin 1 (SIRT1) is a class III histone deacetylase that deacetylates histone and nonhistone proteins to regulate gene transcription and protein function. Because SIRT1 regulates very diverse responses such as apoptosis, insulin sensitivity, autophagy, differentiation, and stem cell pluripotency, it has been a challenge to reconcile how it orchestrates such pleiotropic effects. Here we show that SIRT1 serves as an important regulator of Wnt signaling. We demonstrate that SIRT1 loss of function leads to a significant decrease in the levels of all three Dishevelled (Dvl) proteins. Furthermore, we demonstrate that SIRT1 and Dvl proteins complex in vivo and that inhibition of SIRT1 leads to changes in gene expression of Wnt target genes. Finally, we demonstrate that Wnt-stimulated cell migration is inhibited by a SIRT1 inhibitor. Because the three mammalian Dvl proteins serve as key messengers for as many as 19 Wnt ligands, SIRT1-mediated regulation of Dvl proteins may explain the diverse physiological responses observed in different cellular contexts. Previously, SIRT1 had only been shown to mediate the epigenetic silencing of Wnt antagonists. In contrast, here we report that SIRT1 regulates Dvl protein levels and Wnt signaling in several cellular contexts. These findings demonstrate that SIRT1 is a regulator of transient and constitutive Wnt signaling.