Regulation of AT1R expression through HuR by insulin.
Abstract
Angiotensin II type 1 receptor (AT1R) has a pathophysiological role in hypertension, atherosclerosis and heart failure. Type 2 diabetes is hyperinsulinemic state and a major risk factor for atherosclerosis and hypertension. It is known that hyperinsulinemia upregulates AT1R expression post-transcriptionally by increasing the half-life of AT1R mRNA, but little is known about the mechanism of this effect. In the present study, we first identified AT1R 3'-UTR as a mediator of insulin effect. Using 3'-UTR as a bait, we identified through analysis of insulin-stimulated cell lysates by affinity purification and mass spectrometry HuR as an insulin-regulated AT1R mRNA binding protein. By ribonucleoprotein immunoprecipitation, we found HuR binding to AT1R to be increased by insulin. Overexpression of HuR leads to increased AT1R expression in a 3'-UTR-dependent manner. Both insulin and HuR overexpression stabilize AT1R 3'-UTR and their responsive element within 3'-UTR are located within the same region. Cell fractionation demonstrated that insulin induced HuR translocation from nucleus to cytoplasm increased HuR binding to cytoplasmic AT1R 3'-UTR. Consistent with HuR translocation playing a mechanistic role in HuR effect, a reduction in ...Continue Reading
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RNase-L control of cellular mRNAs: roles in biologic functions and mechanisms of substrate targeting
HuR and other turnover- and translation-regulatory RNA-binding proteins: implications for the kidney
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