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Destabilization of AT(1) receptor mRNA by calreticulin
Georg Nickenig1, Frank Michaelsen, Cornelius Müller
1Klinik und Poliklinik Innere Medizin III, Universität des Saarlandes, Homburg, Germany. nickenig@med-in.uni-sb.de
Abstract:
AT(1) receptor activation leads to vasoconstriction, blood pressure increase, free radical release, and cell growth. AT(1) receptor regulation contributes to the adaptation of the renin-angiotensin system to long-term stimulation and serves as explanation for the involvement of the AT(1) receptor in the pathogenesis of cardiovascular disease. The molecular mechanisms involved in AT(1) receptor regulation are poorly understood. Here, we report that angiotensin II accelerates AT(1) receptor mRNA decay in vascular smooth muscle cells. A cognate mRNA region within the 3' untranslated region at bases 2175 to 2195 governs the inducible decay of the AT(1) receptor mRNA. Sequential protein purifications led to the discovery of a novel mRNA binding protein, calreticulin, which mediates destabilization of the AT(1) receptor mRNA. Angiotensin II-caused phosphorylation of calreticulin enables binding of calreticulin to the AT(1) receptor mRNA at bases 2175 to 2195 and propagates calreticulin-induced acceleration of AT(1) receptor mRNA decay. Thus, a novel mRNA binding protein, calreticulin, is discovered, which causes AT(1) receptor mRNA degradation via binding to a distinct mRNA region in the 3' untranslated region. These findings display a novel mechanism of posttranscriptional mRNA processing.
Insights
Angiotensin II accelerates AT(1) receptor mRNA decay in vascular smooth muscle cells. A novel protein, calreticulin, binds to the mRNA, promoting its degradation and offering new insights into cardiovascular disease mechanisms.
Area of Science:
- Molecular Biology
- Cardiovascular Physiology
- Biochemistry
Background:
- Angiotensin II type 1 (AT(1)) receptor activation influences vasoconstriction, blood pressure, and cell growth, implicating it in cardiovascular disease pathogenesis.
- Regulation of the AT(1) receptor is crucial for renin-angiotensin system adaptation but its molecular mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying AT(1) receptor mRNA regulation.
- To identify proteins involved in the posttranscriptional control of AT(1) receptor expression.
Main Methods:
- Investigated angiotensin II effects on AT(1) receptor mRNA stability in vascular smooth muscle cells.
- Identified a specific mRNA region (bases 2175-2195 in the 3' UTR) governing inducible decay.
- Utilized sequential protein purifications to discover novel mRNA-binding proteins.
Main Results:
- Angiotensin II was found to accelerate the decay of AT(1) receptor mRNA.
- Calreticulin was identified as a novel mRNA-binding protein that destabilizes AT(1) receptor mRNA.
- Angiotensin II-induced calreticulin phosphorylation enhances its binding to the specific mRNA region, accelerating decay.
Conclusions:
- Discovered a novel mechanism of AT(1) receptor mRNA regulation involving calreticulin.
- Calreticulin mediates AT(1) receptor mRNA degradation through binding to a specific 3' UTR region.
- This finding reveals a new pathway in posttranscriptional mRNA processing relevant to cardiovascular function.