Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis
Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis
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DOI：
10.1128/mcb.23.24.9222-9232.2003
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发表时间：
2003-12-01
影响因子：
5.3
通讯作者：
Izumo, S
中科院分区：
文献类型：
--
作者：
Ueyama, T;Kasahara, H;Izumo, S
Nkx2.5（也称为Csx）是同源异型盒基因家族的进化上保守的心脏转录因子。Nkx2.5是早期心脏发育所必需的，因为Nkx2.5缺失小鼠在完成心脏循环之前死亡。为了鉴定发育中心脏Nkx2.5调控的基因，我们使用从胚胎第8.5天的野生型和Nkx2.5缺失心脏中分离的RNA进行消减杂交。我们分离了一个小鼠的cDNA编码myocardin A，这是一个选择性剪接异构体myocardin和最丰富的异构体在心脏从胚胎到成人。在Nkx2.5-null小鼠心脏中，myocardin A和myocardin的表达显著下调。瞬时共转染分析表明，Nkx2.5反式激活心肌蛋白启动子。在畸胎瘤细胞系P19 CL 6中抑制心肌蛋白功能可阻止二甲基亚砜处理后分化为心肌细胞。心肌细胞素A通过血清反应元件反式激活心房利钠因子基因的启动子，该元件被骨形态发生蛋白2和转化生长因子β激活激酶1增强。这些结果表明，myocardin的表达受到Nkx2.5的调节，其功能是心肌发生所必需的。
Nkx2.5 (also known as Csx) is an evolutionarily conserved cardiac transcription factor of the homeobox gene family. Nkx2.5 is required for early heart development, since Nkx2.5-null mice die before completion of cardiac looping. To identify genes regulated by Nkx2.5 in the developing heart, we performed subtractive hybridization by using RNA isolated from wild-type and Nkx2.5-null hearts at embryonic day 8.5. We isolated a mouse cDNA encoding myocardin A, which is an alternative spliced isoform of myocardin and the most abundant isoform in the heart from embryo to adult. The expression of myocardin A and myocardin was markedly downregulated in Nkx2.5-null mouse hearts. Transient-cotransfection analysis showed that Nkx2.5 transactivates the myocardin promoter. Inhibition of myocardin function in the teratocarcinoma cell line P19CL6 prevented differentiation into cardiac myocytes after dimethyl sulfoxide treatment. Myocardin A transactivated the promoter of the atrial natriuretic factor gene through the serum response element, which was augmented by bone morphogenetic protein 2 and transforming growth factor beta-activated kinase 1. These results suggest that myocardin expression is regulated by Nkx2.5 and that its function is required for cardiomyogenesis.