Distinct components of Janus kinase/signal transducer and activator of transcription signaling pathway mediate the regulation of systemic and tissue localized renin-angiotensin system
Distinct components of Janus kinase/signal transducer and activator of transcription signaling pathway mediate the regulation of systemic and tissue localized renin-angiotensin system
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DOI：
10.1210/me.2003-0231
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发表时间：
2004-04-01
影响因子：
--
通讯作者：
Siddiqui, MAQ
中科院分区：
文献类型：
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作者：
Guo, YL;Mascareno, E;Siddiqui, MAQ
为了证明Janus激酶（Jak）/信号转导器和转录激活剂（STAT）信号传导与体内全身或局部肾素-血管紧张素系统的活性之间的联系，我们产生了带有血管紧张素原（ANG）启动子的转基因小鼠，该启动子含有与荧光素酶报告基因融合的野生型或突变型STAT靶位点（St域）。 ANG 启动子驱动的荧光素酶表达依赖于 Jak2 的磷酸化，因为给予 Jak2 的有效抑制剂酪氨酸磷酸化抑制剂 AG490，下调 ANG 启动子活性并消除肝脏中受刺激的内源 ANG mRNA 水平。给小鼠施用血管紧张素II肽导致含有野生型St结构域的动物的肝脏和心脏中荧光素酶显着表达，但在具有突变型St结构域的转基因中则没有显着表达。血管紧张素 II 诱导的信号传导导致肝脏（全身）中 STAT 蛋白的激活，其模式与心脏（局部）不同。 ANG 启动子的诱导型表达似乎是由 p300 与肝脏中的 STAT 5B 以及心脏中的 STAT 3 和 STAT 5A 的物理关联介导的。总而言之，这些结果指出了循环和局部肾素-血管紧张素系统中信号传导机制的差异，并确定了至少两个分子步骤，即 Jak2 的酪氨酰磷酸化和 STAT/St 结构域相互作用，它们是 ANG 基因转录调节的关键。
In an attempt to demonstrate the linkage between the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) signaling and the activity of the systemic or local renin-angiotensin system in vivo, we produced transgenic mice harboring angiotensinogen (ANG) promoter containing the wild-type or mutant STAT target site (St-domain) fused to the luciferase reporter. The ANG-promoter-driven luciferase expression was dependent upon phosphorylation of Jak2, as administration of tyrphostin AG490, a potent inhibitor of Jak2, down-regulated the ANG promoter activity and abolished the stimulated endogenous ANG mRNA level in the liver. Administration of angiotensin II peptide to the mice resulted in prominent expression of luciferase in the liver and heart of animals containing wild type St-domain, but not in transgenes with mutant St-domain. Angiotensin II-induced signaling caused activation of STAT proteins in the liver ( systemic), the pattern of which was distinct from that in the heart ( local). The inducible expression of ANG promoter appears to be mediated by physical association of p300 with STAT 5B in liver and STAT 3 and STAT 5A in heart. Taken together, these results point to the differences in signaling mechanisms in the circulating and localized renin-angiotensin system and identify at least two molecular steps, the tyrosyl phosphorylation of Jak2 and the STAT/St-domain interaction, as pivotal in the regulation of ANG gene transcription.