*Department of Biology, Program in Integrated Bioscience, The University of Akron, Akron, OH 44325, U.S.A.
†The Wistar Institute, Philadelphia, PA 19104, U.S.A.
Clin Sci (Lond). 2014 May;126(10):727-38. doi: 10.1042/CS20130385.
The ACE2 (angiotensin-converting enzyme 2)/Ang-(1-7) [angiotensin-(1-7)]/MAS axis of the RAS (renin-angiotensin system) has emerged as a pathway of interest in treating both cardiovascular disorders and cancer. The MAS protein is known to bind to and be activated by Ang-(1-7); however, the mechanisms of this activation are just starting to be understood. Although there are strong biochemical data regarding the regulation and activation of the AT1R (angiotensin II type 1 receptor) and the AT2R (angiotensin II type 2 receptor), with models of how AngII (angiotensin II) binds each receptor, fewer studies have characterized MAS. In the present study, we characterize the MAS promoter and provide a potential feedback mechanism that could compensate for MAS degradation following activation by Ang-(1-7). Analysis of ENCODE data for the MAS promoter revealed potential epigenetic control by KRAB (Krüppel-associated box)/KAP-1 (KRAB-associated protein-1). A proximal promoter construct for the MAS gene was repressed by the SOX [SRY (sex-determining region on the Y chromosome) box] proteins SRY, SOX2, SOX3 and SOX14, of which SRY is known to interact with the KRAB domain. The KRAB-KAP-1 complex can be tyrosine-nitrated, causing the dissociation of the KAP-1 protein and thus a potential loss of epigenetic control. Activation of MAS can lead to an increase in nitric oxide, suggesting a feedback mechanism for MAS on its own promoter. The results of the present study provide a more complete view of MAS regulation and, for the first time, suggest biochemical outcomes for nitration of the KRAB domain.
肾素-血管紧张素系统（RAS）中的 ACE2（血管紧张素转换酶 2）/Ang-（1-7）[血管紧张素-（1-7）]/MAS 轴已成为治疗心血管疾病和癌症的研究途径。MAS 蛋白已知能与 Ang-（1-7）结合并被其激活；然而，这种激活的机制才刚刚开始被理解。虽然有关于 AT1R（血管紧张素 II 型 1 受体）和 AT2R（血管紧张素 II 型 2 受体）的调节和激活的强有力的生化数据，以及 AngII（血管紧张素 II）结合每个受体的模型，但对 MAS 的研究较少。在本研究中，我们对 MAS 启动子进行了特征描述，并提供了一种潜在的反馈机制，可补偿 Ang-（1-7）激活后 MAS 的降解。对 MAS 启动子的 ENCODE 数据进行分析显示，KAP-1（Krüppel 相关蛋白-1）的 KRAB（Krüppel 相关盒）可能通过表观遗传控制。MAS 基因的近端启动子构建体受到 SOX [SRY（Y 染色体性别决定区）盒]蛋白 SRY、SOX2、SOX3 和 SOX14 的抑制，其中 SRY 已知与 KRAB 结构域相互作用。KRAB-KAP-1 复合物可被酪氨酸硝化，导致 KAP-1 蛋白解离，从而潜在地失去表观遗传控制。MAS 的激活可导致一氧化氮增加，提示 MAS 对其自身启动子存在反馈机制。本研究的结果提供了对 MAS 调节的更完整的认识，并且首次提出了 KRAB 结构域硝化的生化结果。
