β-arrestin1-biased β1-adrenergic receptor signaling regulates microRNA processing.
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2014-02
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Abstract
Rationale
MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin intermediate miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes after activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-arrestins are now appreciated to transduce multiple effector pathways independent of G-protein-mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the β-arrestin-biased βAR agonist, carvedilol, activates cellular pathways in the heart.Objective
Here, we tested whether carvedilol could activate β-arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects.Methods and results
In human cells and mouse hearts, carvedilol upregulates a subset of mature and pre-miRs, but not their pri-miRs, in β1AR-, G-protein-coupled receptor kinase 5/6-, and β-arrestin1-dependent manner. Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs.Conclusions
Our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.Type
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Kim, Il-Man, Yongchao Wang, Kyoung-Mi Park, Yaoping Tang, Jian-Peng Teoh, Joseph Vinson, Christopher J Traynham, Gianluigi Pironti, et al. (2014). β-arrestin1-biased β1-adrenergic receptor signaling regulates microRNA processing. Circulation research, 114(5). pp. 833–844. 10.1161/circresaha.114.302766 Retrieved from https://hdl.handle.net/10161/31641.
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Scholars@Duke
Lan Mao
I. Research:
As the director of mouse physiology laboratory, in charge for the all events related with Dr. Howard Rockman's molecular biology laboratory studies needs.
Participate in research in rodents model:
Perform surgery and serve as co-investigator in studies on transgenic mice with heart failure. Develop models of hypertrophy in small animal using micro-surgical techniques (aortic constriction, left ventricular infarction and abdominal aortocaval fistula) and perform a variety physiological studies, obtain and analysis data on hemodynamic study and prepare tissue specimens for father molecular biological study.
Develop and apply surgical techniques for in vivo myocardial function study on small animal, such as, using new developed devices study in vivo mice cardiac function (pressure-volume lop), instrumented mice for conscious blood pressure measure or administration of medicine---carotid artery or gull duck catheterization, and conscious mice echocardiography.
Develop techniques for micro-injection of proteins and vectors in to mouse left ventricle, coronary artery and portal vein.
II. Teaching
10% of time allocated/spent---
Train postdoctoral fellows, visiting scientists and students from all over the world in laboratory procedure involving, including endotracheal intubations, cardiac catheterization, coronary occlusion and intrathoracic/intra-abdominal surgical procedures.
Teach methods of data recording and analysis using laboratory equipment and computer programs, echocardiography apply and measurement.
III. Consultant
Consult and teach microsurgical techniques related on small animals such as, rabbits, rat, hamsters and mice, like mice heart-lung transplantation, portal vein injection and mini-pump implant.
Co-laboratory with large range of Universities and Research Institutes from United States an other countries.
Howard Allan Rockman
Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure
Overall Research Direction: The major focus of this laboratory is to understand the molecular mechanisms of hypertrophy and heart failure. My laboratory uses a strategy that combines state of the art molecular techniques to generate transgenic and gene targeted mouse models, combined with sophisticated physiologic measures of in vivo cardiac function. In this manner, candidate molecules are either selectively overexpressed in the mouse heart or genes ablated followed by an in-depth analysis of the physiological phenotype. To model human cardiac disease, we have created several models of cardiac overload in the mouse using both microsurgical techniques and genetic models of cardiac dysfunction.
Areas of Research
1) Signaling: G protein-coupled receptor signaling in hypertrophy and heart failure focusing on the concept of biased signaling of 7 transmembrane receptors.
2) Molecular physiology: In depth physiological analysis of cardiac function in genetically altered mice to understand the role of G protein-coupled receptor signaling pathways on the development of heart failure in vivo.
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