Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Republic of Korea.
Sci Rep. 2017 Oct 13;7(1):13174. doi: 10.1038/s41598-017-13487-w.
Angiotensin-converting enzyme (ACE) is an evolutionarily conserved peptidyl dipeptidase. Mammalian ACE converts angiotensin I to the active vasoconstrictor angiotensin II, thus playing a critical role for homeostasis of the renin-angiotensin system. In Drosophila, the ACE homolog Ance is expressed in specific regions of developing organs, but its regulatory mechanism has not been identified. Here we provide evidence that Ance expression is regulated by a combination of Mad and Pannier (Pnr) in imaginal discs. We demonstrate that Ance expression in eye and wing discs depends on Dpp signaling. The Mad binding site of Ance regulatory region is essential for Ance expression. Ance expression in imaginal discs is also regulated by the GATA family transcription factor Pnr. Pnr directly regulates Ance expression by binding to a GATA site of Ance enhancer. In addition, Pnr and Mad physically and genetically interact. Ance null mutants are morphologically normal but show genetic interaction with dpp mutants. Furthermore, we show that human SMAD2 and GATA4 physically interact and ACE expression in HEK293 cells is regulated by SMAD2 and GATA4. Taken together, this study reveals a cooperative mechanism of Ance regulation by Mad and Pnr. Our data also suggest a conserved transcriptional regulation of human ACE.
血管紧张素转化酶（ACE）是一种进化上保守的肽二肽酶。哺乳动物 ACE 将血管紧张素 I 转化为活性血管收缩素 II，从而在肾素-血管紧张素系统的动态平衡中发挥关键作用。在果蝇中，ACE 同源物 Ance 在发育器官的特定区域表达，但尚未确定其调节机制。在这里，我们提供证据表明，Ance 的表达受 imaginal discs 中 Mad 和 Pannier（Pnr）的组合调控。我们证明，眼盘和翅盘的 Ance 表达依赖于 Dpp 信号。Ance 调控区的 Mad 结合位点对于 Ance 的表达是必需的。Pnr 是 GATA 家族转录因子，也可通过结合 Ance 增强子中的 GATA 位点直接调控 Ance 的表达。此外，Pnr 和 Mad 在物理和遗传上相互作用。Ance 缺失突变体在形态上是正常的，但与 dpp 突变体存在遗传相互作用。此外，我们还表明，人 SMAD2 和 GATA4 可相互作用，HEK293 细胞中的 ACE 表达受 SMAD2 和 GATA4 调控。总之，这项研究揭示了 Mad 和 Pnr 对 Ance 调控的协同机制。我们的数据还表明，人类 ACE 的转录调控是保守的。
