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Submitted on June 18, 2003
Accepted on January 7, 2004
Center for cardiovascular & Muscle Research and Department of Anatomy & Cell Biology, State University of New York Downstate Medical Center, Brooklyn, N.Y. 11203
* To whom correspondence should be addressed. E-mail: MAQ.Siddiqui{at}downstate.edu.
In an attempt to demonstrate the linkage between the Jak/STAT signaling and the activity of the systemic or local renin-angiotensin system (RAS) 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 (AngII) 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. Ang 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 RAS 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.
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