• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Pigment cell research >Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease-associated mutations
【24h】

Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease-associated mutations

机译：Pax3靶基因识别通过不同模式发生，这些模式受疾病相关突变的影响不同

获取原文
获取原文并翻译 | 示例
       
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The paired box protein Pax3 is an essential regulator of muscle and neural crest-derived cell types, including melanocytes. Within this lineage, Pax3 has been shown to regulate the genes encoding microphthalmia-associated transcription factor (Mitf) and tyrosinase-related protein-1 (Trp-1), despite each having dissimilar Pax3 recognition sequences. We have, therefore, examined the structural requirements for Pax3 binding to the MITF and TRP-1 promoter elements, focusing on the contribution of the paired domain and homeodomain to Pax3 target site recognition. Unexpectedly, although the MITF element is characterized by suboptimal recognition motifs for the paired domain and homeodomain, it sustains a higher level of Pax3 binding than TRP-1, which contains a canonical paired domain site. The basis for this difference involves a context-dependent cooperative binding event requiring both the paired domain and homeodomain, while the paired domain alone is sufficient for TRP-1 recognition. Significantly, the analysis of Waardenburg syndrome mutations reveals marked disparity in their effects on MITF and TRP-1 binding that further underscores mechanistic differences in their interaction with Pax3. Importantly, these mutations also exert distinct effects on the ability of Pax3 to regulate reporter genes fused to either the MITF or TRP-1 promoters. Our results, therefore, establish that Pax3 can regulate target genes through alternate modes of DNA recognition that are differentially impacted by disease-causing mutations, which together have important implications for understanding Pax3-regulated gene networks.
机译：配对盒蛋白Pax3是肌肉和神经neural衍生细胞类型（包括黑素细胞）的重要调节剂。在该谱系中，尽管Pax3各自具有不同的Pax3识别序列，但已显示其可调节编码小眼症相关转录因子（Mitf）和酪氨酸酶相关蛋白1（Trp-1）的基因。因此，我们研究了Pax3与MITF和TRP-1启动子元件结合的结构要求，重点是配对域和同源域对Pax3目标位点识别的贡献。出乎意料的是，尽管MITF元件的特征是配对域和同源域的亚最佳识别基序，但与TRP-1相比，它具有更高的Pax3结合水平，而TRP-1包含规范的配对域位点。这种差异的基础涉及需要配对域和同源域的依赖于上下文的协作绑定事件，而仅配对域就足以识别TRP-1。值得注意的是，对Waardenburg综合征突变的分析表明，它们对MITF和TRP-1结合的影响存在明显差异，这进一步强调了它们与Pax3相互作用的机理差异。重要的是，这些突变还对Pax3调节融合至MITF或TRP-1启动子的报告基因的能力产生了明显影响。因此，我们的结果证实，Pax3可以通过DNA识别的替代模式调节靶基因，而这些替代模式受致病突变的影响不同，这些突变对理解Pax3调控的基因网络具有重要意义。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号