Transcriptional regulation of the homeobox gene Mixl1 by TGF-β and FoxH1
Transcriptional regulation of the homeobox gene Mixl1 by TGF-β and FoxH1
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DOI：
10.1016/j.bbrc.2005.06.044
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发表时间：
2005-08-12
影响因子：
3.1
通讯作者：
Robb, L
中科院分区：
文献类型：
--
作者：
Hart, AH;Willson, TA;Robb, L
Mixl 1是一种配对型同源结构域蛋白，在小鼠胚胎的形态发生和内胚层分化中起着至关重要的作用。为了了解Mixl 1如何指导胚胎发生，我们在转录水平上研究了Mixl 1表达的调控。在HepG 2细胞中，包含Mixl 1启动子的基因组片段赋予了强烈的TGF-β诱导的转录，这依赖于DNA结合蛋白FoxH 1的存在。对Mixll启动子的进一步分析鉴定了含有TGF-β反应性所需的SMAD-和FoxH 1-结合位点的近端反应元件（PRE）。PRE也对Nodal的信号传导有反应，Nodal是正常胚胎模式所需的TGF-β配体。这些结果首次证明了TGF-β配体在调节哺乳动物Mixl 1中的功能性作用，鉴定了FoxH 1作为必需的转录共激活因子，并暗示Nodal作为Mixl 1在中内胚层形态发生中的胚胎调节因子。(c)2005年爱思唯尔公司All rights reserved.
Mixl1 is a paired-type homeodomain protein that plays a crucial role in morphogenesis and endoderm differentiation in the murine embryo. To understand how Mixl1 directs embryogenesis, we studied the regulation of Mixl1 expression at a transcriptional level. In HepG2 cells, a genomic fragment encompassing the Mixl1 promoter conferred strong TGF-beta-induced transcription that was dependent on the presence of the DNA-binding protein FoxH1. Further analysis of the Mixl1 promoter identified a proximal response element (PRE) containing SMAD- and FoxH1-binding sites required for TGF-beta responsiveness. The PRE was also responsive to signalling by Nodal, a TGF-beta ligand required for normal embryonic patterning. These results demonstrate for the first time a functional role for TGF-beta ligands in regulation of mammalian Mixl1, identify FoxH1 as an essential transcriptional co-activator, and implicate Nodal as the embryonic regulator of Mixl1 in mesendoderm morpbogenesis. (c) 2005 Elsevier Inc. All rights reserved.