Competition between negative acting YY1 versus positive acting serum response factor and tinman homologue Nkx-2.5 regulates cardiac alpha-actin promoter activity.
Competition between negative acting YY1 versus positive acting serum response factor and tinman homologue Nkx-2.5 regulates cardiac alpha-actin promoter activity.
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DOI：
10.1210/mend.11.6.0015
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发表时间：
1997-06
影响因子：
--
通讯作者：
C. Chen;R. Schwartz
中科院分区：
文献类型：
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作者：
C. Chen;R. Schwartz
肌节α-肌动蛋白基因的转录在骨骼肌和心肌发育过程中通过涉及多种合作和拮抗转录因子的微调控制机制受到发育调节。这些因子识别的顺式作用 DNA 元件中有血清反应元件 (SRE) 的 CC(A/T)6GG 序列，它存在于许多生长因子诱导型和肌原性特定基因中。我们最近表明，心原性同源域因子 Nkx-2.5 作为血清反应因子 (SRF) 的正作用辅助因子，共同提供心脏 α-肌动蛋白启动子的强转录激活。此外，Nkx-2.5 和 SRF 协同激活 10T1/2 成纤维细胞中的内源性鼠心脏 α-肌动蛋白基因，其机制涉及 SRF 和 Nkx-2.5 在 α-肌动蛋白启动子的完整 SRE 上的共缔合。在这里，我们发现禽类心脏 α-肌动蛋白启动子的第二个 SRE 充当 Nkx-2.5、SRF 和含有 GLI-Kruppel 样因子 YY1 的锌指的结合位点。 YY1 的表达抑制心脏 α-肌动蛋白启动子活性，而 Nkx-2.5 和 SRF 的共表达能够部分逆转 YY1 的抑制。 Nkx-2.5/SRF 复合物对 YY1 结合的取代是通过跨 CaSRE2 的互斥结合发生的。 YY1 和 Nkx-2.5/SRF 之间的相互作用和功能拮抗可能构成了在心脏发生过程中调节心脏 α-肌动蛋白基因表达的发育和生理调节机制。
Transcription of sarcomeric alpha-actin genes is developmentally regulated during skeletal and cardiac muscle development through fine-tuned control mechanisms involving multiple cooperative and antagonistic transcription factors. Among the cis-acting DNA elements recognized by these factors is the sequence CC(A/T)6GG of the serum response element (SRE), which is present in a number of growth factor-inducible and myogenic specified genes. We recently showed that the cardiogenic homeodomain factor, Nkx-2.5, served as a positive acting accessory factor for serum response factor (SRF) and together provided strong transcriptional activation of the cardiac alpha-actin promoter. In addition, Nkx-2.5 and SRF collaborated to activate the endogenous murine cardiac alpha-actin gene in 10T1/2 fibroblasts, by a mechanism that involved coassociation of SRF and Nkx-2.5 on intact SREs of the alpha-actin promoter. Here, we show that the second SRE of the avian cardiac alpha-actin promoter served as a binding site for Nkx-2.5, SRF, and zinc finger containing GLI-Kruppel-like factor, YY1. Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression. Displacement of YY1 binding by Nkx-2.5/SRF complex occurs through mutually exclusive binding across the CaSRE2. The interplay and functional antagonism between YY1 and Nkx-2.5/SRF might constitute a developmental as well as a physiologically regulated mechanism that modulates cardiac alpha-actin gene expression during cardiogenesis.