The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors
The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors
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DOI：
10.1093/emboj/16.18.5687
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发表时间：
1997-09-15
期刊：
影响因子：
11.4
通讯作者：
Nemer, M
中科院分区：
文献类型：
--
作者：
Durocher, D;Charron, F;Nemer, M
组织限制性加塔-4转录因子和Nkx 2 -5同源结构域蛋白是心前细胞的两个早期标志物，两者都是心脏形成所必需的，但都不能启动心脏发生。加塔-4或Nkx 2 -5的过表达增强了定向前体的心脏发育，表明它们各自与心脏辅因子相互作用。我们通过使用心脏心房利钠因子（ANF）启动子（Nkx 2 -5的唯一已知靶点）的转录和结合测定来测试加塔-4和Nkx 2 -5是否是彼此的辅因子，加塔-4和Nkx 2 -5的共表达导致异源细胞中ANF启动子的协同激活。协同作用涉及体外和体内观察到的Nkx 2 -5-加塔-4的物理相互作用。其定位于加塔-4的C-末端锌指和G-末端延伸;类似地，加塔-4结合需要Nkx 2 -5的G-末端延伸的同源结构域，结构/功能研究表明，加塔-4与Nkx 2 -5的G-末端自动阻遏结构域的结合可诱导构象变化，从而暴露Nkx 2 -5活化结构域，加塔-6不能代替加塔-4与Nkx 2 -5相互作用。这种相互作用可能赋予加塔因子功能特异性，并在早期心脏发生的两个关键途径之间提供合作串扰。考虑到加塔蛋白和NK 2类成员在其他组织中的共表达，加塔/Nkx伙伴关系可能代表器官发生期间转录因子相互作用的范例。
The tissue-restricted GATA-4 transcription factor and Nkx2-5 homeodomain protein are two early markers of precardiac cells, Both are essential for heart formation, but neither can initiate cardiogenesis. Overexpression of GATA-4 or Nkx2-5 enhances cardiac development in committed precursors, suggesting each interacts with a cardiac cofactor, We tested whether GATA-4 and Nkx2-5 are cofactors for each other by using transcription and binding assays with the cardiac atrial natriuretic factor (ANF) promoter-the only known target for Nkx2-5, Co-expression of GATA-4 and Nkx2-5 resulted in synergistic activation of the ANF promoter in heterologous cells, The synergy involves physical Nkx2-5-GATA-4 interaction, seen in vitro and in vivo, which maps to the C-terminal zinc finger of GATA-4 and a G-terminus extension; similarly, a G-terminally extended homeodomain of Nkx2-5 is required for GATA-4 binding, Structure/function studies suggest that binding of GATA-4 to the G-terminus autorepressive domain of Nkx2-5 may induce a conformational change that unmasks Nkx2-5 activation domains, GATA-6 cannot substitute for GATA-4 for interaction with Nkx2-5. This interaction may impart functional specificity to GATA factors and provide cooperative crosstalk between two pathways critical for early cardiogenesis. Given the co-expression of GATA proteins and NK2 class members in other tissues, the GATA/Nkx partnership may represent a paradigm for transcription factor interaction during organogenesis.