Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling
Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling
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DOI：
10.1242/jcs.000067
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发表时间：
2007-04-15
影响因子：
4
通讯作者：
Kaneda, Yasufumi
中科院分区：
文献类型：
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作者：
Hayashi, Masanori;Nimura, Keisuke;Kaneda, Yasufumi
碱性螺旋-环-螺旋(BHLH)转录因子是间充质分化的关键调控因子。目前的研究表明，bHLH转录因子Twist-1的过表达抑制了骨形态发生蛋白(BMP)诱导的成骨细胞分化，而下调内源性Twist-1则增强了BMP信号转导。当Twist-1与E47结合时，BMP信号转导受到最大程度的抑制，从而显著增强了Twist-1的稳定性。免疫共沉淀实验表明，在稳定表达Twist-1的MC3T3-E1细胞中，Twist-1与Smad4和组蛋白脱乙酰基酶(HDAC)1形成了复合体。在HDAC抑制剂曲古斯丁的作用下，碱性磷酸酶、Runx2和骨桥蛋白等成骨因子增加。这些结果提示Twist-1通过将HDAC1招募到Smad4来抑制BMP信号转导。此外，Id1通过诱导Twist1降解来克服Twist-1对BMP信号转导的抑制作用。这些发现表明Twist-1可以作为BMP信号的抑制因子，而Id1可以通过抑制Twist-1功能的正反馈环来调节BMP信号。因此，这两个分子可能通过控制BMP信号来调节间充质细胞向成骨细胞等后代的分化。
Basic helix-loop-helix ( bHLH) transcription factors are known as key regulators for mesenchymal differentiation. The present study showed that overexpression of Twist-1, a bHLH transcription factor, suppresses bone morphogenetic protein (BMP)- induced osteoblast differentiation, and downregulation of endogenous Twist-1 enhances BMP signaling. Maximal inhibition of BMP signaling was observed when Twist-1 was bound to E47, which markedly enhanced the stability of Twist-1. Co-immunoprecipitation assays revealed that Twist-1 formed a complex with Smad4 and histone deacetylase ( HDAC) 1 in MC3T3- E1 cells stably expressing Twist-1. With trichostatin, an HDAC inhibitor, osteogenic factors such as alkaline phosphatase, Runx2 and osteopontin increased. Those results suggested that Twist-1 inhibited BMP signaling by recruiting HDAC1 to Smad4.Furthermore, the inhibitory effects of Twist-1 on BMP signaling were overcome by Id1 through induction of Twist1 degradation. These findings suggest that Twist-1 can act as an inhibitor of BMP signaling, and Id1 can regulate BMP signaling through a positive feedback loop repressing Twist- 1 function. These two molecules may therefore regulate differentiation of mesenchymal cells into progeny such as osteoblasts by controlling BMP signaling.