miR199a-3p regulates P53 by targeting CABLES1 in mouse cardiac c-kit cells to promote proliferation and inhibit apoptosis through a negative feedback loop
Authors: Jian Wu
Meng Sun
Jingbo Hou
Xinxin Liu
Zhongyue Pu
Chao Wang
Shuo Zhang
Wenjuan Du
Bo Yu
Jingjin Liu
Yongshun Wang
Jinjin Cui
Journal: Stem Cell Research & Therapy (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: MicroRNAs; cardiac c-kit+ cells; proliferation; apoptosis; miR199a-3p
Affiliations: Cardiology Department, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China., Key Laboratories of the Education Ministry for Myocardial Ischemia Mechanisms and Treatment, Harbin, Heilongjiang Province, China., Cardiology Department, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, 150086, China. ., Key Laboratories of the Education Ministry for Myocardial Ischemia Mechanisms and Treatment, Harbin, Heilongjiang Province, China. .

Abstract:  Background: MicroRNAs (miRNAs) have emerged as crucial factors that regulate proliferation and apoptosis of cardiac c-kit+ cells. Although much is known about their role in maintaining cardiac c-kit+ cell pluripotency, the mechanisms by which they affect cell fate decisions that are an essential part of the repair of heart failure remain poorly understood. Methods: Cardiac c-kit+ cells were obtained from Balb/c mice and cultured in vitro. Lentiviral vectors of miR199a-3p, its corresponding anti-miRNA, or short hairpin RNA against Cables1 were transfected into cells. The proliferation of cardiac c-kit+ cells was evaluated using EdU and flow cytometry. Furthermore, we examined cell apoptosis by flow cytometry under treatment with 200nM angiotensin II for 48 h. The levels of miR199a-3p and Cables1 mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to examine the expression of Cables1 and P53 proteins. Results: We demonstrated a significantly decreased expression of miR199a-3p in heart failure samples compared with healthy donors. Meanwhile, we identified miR199a-3p as a proliferation- and apoptosis-associated regulator impacted through Cdk5 and Abl enzyme substrate 1 (CABLES1) targeting, and also attributed their repression to P53 protein expression. We further demonstrated that P53 induced miR199a-3p expression and, in turn, miR199-3p decreased P53 activity. Conclusion: Collectively, our findings uncover one new mechanism by which P53 induced miR199a-3p expression and, in turn, miR199-3p decreased P53 activity. Therefore, miR199a-3p and P53 are coupled through CABLES1 and comprise a novel negative feedback loop that likely contributes to cardiac c-kit+ cell proliferation and apoptosis. 

Retracted: No

PubPeer comments:
 More hard to explain duplications. Data are reused from an earlier publication from the same group (Wang Y et al., 2016, Sci Rep), and have changed to something completely different. Please note that these issues were detected in a screen for duplications in papers citing a publication from the Anversa group containing falsified data about cardiac stem cells (Bearzi C et al., 2007, PNAS). ![file] ![file] , 
 Dear Tabebuia Rosea Thanks for your careful checking of our online manuscript. The figures are incorrectly presented. Our figures in Figure 5b and 6c are confused with another side by side research project. We would like to convey our sincerely apology for any inconvenience caused and bothering considering the oversight on the manuscripts. The errors have now been corrected and do not affect the results or conclusion of this work. Regards Jingjin Liu ,