Context-dependent Transcriptional Cooperation Mediated by Cardiac Transcription Factors Csx/Nkx-2.5 and GATA-4*
Context-dependent Transcriptional Cooperation Mediated by Cardiac Transcription Factors Csx/Nkx-2.5 and GATA-4*
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DOI：
10.1074/jbc.274.12.8231
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发表时间：
1999-03
期刊：
影响因子：
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通讯作者：
I. Shiojima;I. Komuro;T. Oka;Y. Hiroi;T. Mizuno;E. Takimoto;K. Monzen;R. Aikawa;H. Akazawa;T. Yamazaki;S. Kudoh;Y. Yazaki
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文献类型：
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作者：
I. Shiojima;I. Komuro;T. Oka;Y. Hiroi;T. Mizuno;E. Takimoto;K. Monzen;R. Aikawa;H. Akazawa;T. Yamazaki;S. Kudoh;Y. Yazaki
虽然心脏同源框基因Csx/Nkx-2.5对心脏的正常发育是必不可少的，但人们对其调控机制知之甚少。在寻找CSx/Nkx-2.5下游靶基因的过程中，我们发现心钠素(ANP)基因启动子被CSx/Nkx-2.5强烈反式激活。对ANP启动子的缺失和突变分析表明，位于Csx/Nkx-2.5上的Csx/Nkx-2.5结合元件(−)是Csx/Nkx-2.5高度反式激活所必需的。我们还发现CSX/NKX-2.5和GATA-4显示了心钠素启动子的协同转录激活，与以前的报道不同(Durocher，D.，Charron，F.，Warren，R.，Schwartz，R.J.和Nemer，M.(1997)EMBO J.16,5687-5696；Lee，Y.，Shioi，T.，Kasahara，H.，Jobe，S.M.，Wiese，R.J.，Markham，B.和Izumo，S(1998)Mol。牢房。比奥尔。18,3120-3129)，这种协同作用依赖于CSX/NKX-2.5与NKE2的结合，而不依赖于GATA-4与DNA的相互作用。虽然GATA-4也增强了CSX/NKX-2.5诱导的含有多聚化CSX/NKX-2.5结合位点的人工启动子的反式激活，但CSX/NKX-2.5抑制了GATA-4诱导的依赖于GATA-4的启动子的反式激活。这些结果表明，CSX/NKX-2.5和GATA-4介导的协同转录调控是启动子上下文依赖的，提示复杂-反式相互作用可能微调心肌细胞中的基因表达。
Although the cardiac homeobox geneCsx/Nkx-2.5 is essential for normal heart development, little is known about its regulatory mechanisms. In a search for the downstream target genes of Csx/Nkx-2.5, we found that the atrial natriuretic peptide (ANP) gene promoter was strongly transactivated by Csx/Nkx-2.5. Deletion and mutational analyses of the ANP promoter revealed that the Csx/Nkx-2.5-binding element (NKE2) located at −240 was required for high level transactivation by Csx/Nkx-2.5. We also found that Csx/Nkx-2.5 and GATA-4 displayed synergistic transcriptional activation of the ANP promoter, and in contrast to previous reports (Durocher, D., Charron, F., Warren, R., Schwartz, R. J., and Nemer, M. (1997) EMBO J. 16, 5687–5696; Lee, Y., Shioi, T., Kasahara, H., Jobe, S. M., Wiese, R. J., Markham, B., and Izumo, S (1998) Mol. Cell. Biol. 18, 3120–3129), this synergism was dependent on binding of Csx/Nkx-2.5 to NKE2, but not on GATA-4-DNA interactions. Although GATA-4 also potentiated the Csx/Nkx-2.5-induced transactivation of the artificial promoter that contains multimerized Csx/Nkx-2.5-binding sites, Csx/Nkx-2.5 reduced the GATA-4-induced transactivation of the GATA-4-dependent promoters. These findings indicate that the cooperative transcriptional regulation mediated by Csx/Nkx-2.5 and GATA-4 is promoter context-dependent and suggest that the complexcis-trans interactions may fine-tune gene expression in cardiac myocytes.