Unique and complimentary activities of the Gli transcription factors in Hedgehog signaling
Unique and complimentary activities of the Gli transcription factors in Hedgehog signaling
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DOI：
10.1016/j.yexcr.2006.02.019
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发表时间：
2006-07-01
影响因子：
3.7
通讯作者：
Bushman, Wade
中科院分区：
文献类型：
--
作者：
Lipinski, Robert J.;Gipp, Jerry J.;Bushman, Wade
glii转录因子家族（Gli1、2和3）通过调节下游靶基因的表达介导Hedgehog形态发生信号。Hedgehog信号的异常严重影响脊椎动物的发育。出生后，Hedgehog信号被认为在愈合和修复过程中发挥关键作用，并且不适当的通路激活与几种类型的癌症有关。为了更好地了解Gli转录因子的上游调控，以及它们在调节Hedgehog靶基因表达中的独特和组合作用，我们对Gli突变小鼠的胚胎成纤维细胞（mef）进行了表征。Sonic Hedgehog （Shh）肽刺激野生型mef可诱导Hedgehog靶基因Gli1、Ptc1和Hip1的独特谱。Gli2功能丧失与sh诱导的靶基因表达减少有关，而Gli3功能丧失与基础和sh诱导的靶基因表达增加有关。Gli1的单独缺失对靶基因的诱导没有影响，但当Gli2或Gli3缺失时，sh诱导的靶基因表达会减少。此外，Gli1的过表达诱导了Gli2(-/-)3(-/-) mef中的靶基因表达，而Shh刺激则没有。使用仅表达Gli2或Gli3的mef，我们发现环巴胺和PKA激活剂forskolin均抑制Gli2和Gli3介导的靶基因诱导。这些结果表明，Gli2和Gli3具有共同的调控机制，在直接、独立调控Hedgehog靶基因表达的同时，也调控Gli1的表达，在特定环境下协同促进靶基因的激活。(c) 2006爱思唯尔公司版权所有。
The Gli family of transcription factors (Gli1, 2 and 3) mediate the Hedgehog morphogenetic signal by regulating the expression of downstream target genes. Aberrations in Hedgehog signaling seriously affect vertebrate development. Postnatally, Hedgehog signaling has been postulated to play a pivotal role in healing and repair processes and inappropriate pathway activation has been implicated in several types of cancers. To better understand both the upstream regulation of the Gli transcription factors, as well as their unique and combinatorial roles in regulating the expression of Hedgehog target genes, we have characterized embryonic fibroblasts (MEFs) from Gli mutant mice. Stimulation of wild-type MEFs by Sonic Hedgehog (Shh) peptide elicited unique profiles of induction of Hedgehog target genes Gli1, Ptc1, and Hip1. Gli2 loss-of-function was associated with diminished Shh-induced target gene expression, while Gli3 loss-of-function was associated with increased basal and Shh-induced target gene expression. The loss of Gli1 alone had no effect on target gene induction but did diminish Shh-induced target gene expression when combined with the loss of Gli2 or Gli3. Additionally, overexpression of Gli1 induced target gene expression in Gli2(-/-)3(-/-) MEFs, while Shh stimulation did not. Using MEFs expressing only Gli2 or Gli3, we found that both cyclopamine and the PKA activator forskolin inhibited target gene induction mediated by Gli2 and Gli3. These results demonstrate that Gli2 and Gli3 share common regulatory mechanisms and modulate Hedgehog target gene expression directly and independently while also regulating Gli1 expression, which in specific contexts, coordinately contributes to target gene activation. (c) 2006 Elsevier Inc. All rights reserved.