Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling.
Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling.
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发表时间：
1999-09
期刊：
影响因子：
4.6
通讯作者：
H. Sasaki;Y. Nishizaki;C. Hui;M. Nakafuku;H. Kondoh
中科院分区：
文献类型：
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作者：
H. Sasaki;Y. Nishizaki;C. Hui;M. Nakafuku;H. Kondoh
Gli家族锌指蛋白是脊椎动物中Sonic hedgehog（Shh）信号传导的介质。然而，关于这些Gli蛋白如何参与Shh信号通路的问题仍然没有答案。在这项研究中，与Gli 2蛋白相关的调节活动与Shh信号进行了研究。虽然Gli 2作为一个弱的转录激活因子，它实际上是一个复合的积极和消极的调控结构域。在培养的细胞中，截短C-末端一半的激活结构域导致具有阻遏物活性的蛋白质，而去除N末端的阻遏结构域将Gli 2转化为强激活剂。在转基因小鼠胚胎中，与全长蛋白质不同，N-末端截短的Gli 2激活背神经管中的Shh靶基因HNF 3 β，从而模拟Shh信号的作用。这表明，通过调节N-末端阻遏结构域揭示Gli 2的强激活潜力是Shh信号传导的关键机制之一。一个类似的调节机制，涉及的N-末端区域也被发现为Gli 3，但没有为Gli 1。当来自脊索的Shh信号被神经板接收时，广泛表达的Gli 2和Gli 3蛋白可能在腹侧细胞中转化为它们的活性形式，导致它们的靶基因（包括Gli 1）的转录激活。
Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling in vertebrates. The question remains unanswered, however, as to how these Gli proteins participate in the Shh signaling pathway. In this study, regulatory activities associated with the Gli2 protein were investigated in relation to the Shh signaling. Although Gli2 acts as a weak transcriptional activator, it is in fact a composite of positive and negative regulatory domains. In cultured cells, truncation of the activation domain in the C-terminal half results in a protein with repressor activity, while removal of the repression domain at the N terminus converts Gli2 into a strong activator. In transgenic mouse embryos, N-terminally truncated Gli2, unlike the full length protein, activates a Shh target gene, HNF3beta, in the dorsal neural tube, thus mimicking the effect of Shh signal. This suggests that unmasking of the strong activation potential of Gli2 through modulation of the N-terminal repression domain is one of the key mechanisms of the Shh signaling. A similar regulatory mechanism involving the N-terminal region was also found for Gli3, but not for Gli1. When the Shh signal derived from the notochord is received by the neural plate, the widely expressed Gli2 and Gli3 proteins are presumably converted to their active forms in the ventral cells, leading to activation of transcription of their target genes, including Gli1.