NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes.
NKX2-5 regulates the expression of beta-catenin and GATA4 in ventricular myocytes.
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DOI：
10.1371/journal.pone.0005698
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发表时间：
2009-05-28
期刊：
影响因子：
3.7
通讯作者：
Van Arsdell GS
中科院分区：
文献类型：
--
作者：
Riazi AM;Takeuchi JK;Hornberger LK;Zaidi SH;Amini F;Coles J;Bruneau BG;Van Arsdell GS
控制心脏发生的分子途径在时间和空间上受到主转录调节因子如NKX 2 -5、Isl 1、MEF 2C、GATA 4和β-连环蛋白的调节。这些因素及其下游目标之间的相互作用尚未完全了解。在此，我们研究了NKX 2 -5对人胎儿心肌细胞β-catenin和GATA 4的调节。使用反义抑制，我们破坏了NKX 2 -5的表达，并研究了心脏相关基因表达的变化。NKX 2 -5的下调导致β-catenin增加，而GATA 4减少。我们证明了这种调节是通过NKX 2 -5与β-连环蛋白和GATA 4基因启动子区的特异性元件（NKE）结合而实现的。使用启动子-荧光素酶报告基因测定结合NKEs的突变分析，我们证明了所鉴定的NKX 2 -5结合位点对于NKX 2 -5抑制β-连环蛋白和上调GATA 4是必需的。这项研究表明，NKX 2 -5调节β-catenin和GATA 4在发育中的人心肌细胞的转录活性。
The molecular pathway that controls cardiogenesis is temporally and spatially regulated by master transcriptional regulators such as NKX2-5, Isl1, MEF2C, GATA4, and β-catenin. The interplay between these factors and their downstream targets are not completely understood. Here, we studied regulation of β-catenin and GATA4 by NKX2-5 in human fetal cardiac myocytes. Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased β-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the β-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of β-catenin, and upregulation of GATA4 by NKX2-5. This study suggests that NKX2-5 modulates the β-catenin and GATA4 transcriptional activities in developing human cardiac myocytes.
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