A Circular RNA Binds To and Activates AKT Phosphorylation and Nuclear Localization Reducing Apoptosis and Enhancing Cardiac Repair

Overview

Journal Theranostics

Date 2017 Nov 8

PMID 29109781

Citations 211

Authors

Yan Zeng

William W Du

Yingya Wu

Zhenguo Yang

Faryal Mehwish Awan

Xiangmin Li

Weining Yang

Chao Zhang

Qi Yang

Albert Yee

Yu Chen

Fenghua Yang

Huan Sun

Ren Huang

Albert J Yee

Ren-Ke Li

Zhongkai Wu

Peter H Backx

Burton B Yang

Affiliations

Soon will be listed here.

Abstract

As central nodes in cardiomyocyte signaling, nuclear AKT appears to play a cardio-protective role in cardiovascular disease. Here we describe a circular RNA, circ-Amotl1 that is highly expressed in neonatal human cardiac tissue, and potentiates AKT-enhanced cardiomyocyte survival. We hypothesize that circ-Amotl1 binds to PDK1 and AKT1, leading to AKT1 phosphorylation and nuclear translocation. In primary cardiomyocytes, epithelial cells, and endothelial cells, we found that forced circ-Amotl1 expression increased the nuclear fraction of pAKT. We further detected increased nuclear pAKT in circ-Amotl1-treated hearts. In vivo, circ-Amotl1 expression was also found to be protective against Doxorubicin (Dox)-induced cardiomyopathy. Putative PDK1- and AKT1-binding sites were then identified . Blocking oligonucleotides could reverse the effects of exogenous circ-Amotl1. We conclude that circ-Amotl1 physically binds to both PDK1 and AKT1, facilitating the cardio-protective nuclear translocation of pAKT.

Citing Articles

Circular RNAs in neurological conditions - computational identification, functional validation, and potential clinical applications.

Hatzimanolis O, Sykes A, Cristino A Mol Psychiatry. 2025; .

PMID: 39966624 DOI: 10.1038/s41380-025-02925-1.

Circular RNAs in cancer stem cells: Insights into their roles and mechanisms (Review).

Yang L, Yi Y, Mei Z, Huang D, Tang S, Hu L Int J Mol Med. 2025; 55(3).

PMID: 39930823 PMC: 11781527. DOI: 10.3892/ijmm.2025.5491.

Circular RNAs in cancer.

Guo Y, Huang Q, Heng Y, Zhou Y, Chen H, Xu C MedComm (2020). 2025; 6(2):e70079.

PMID: 39901896 PMC: 11788016. DOI: 10.1002/mco2.70079.

CircRNA-mediated regulation of cardiovascular disease.

Cheng K, Wang S, Lan T, Mao Z, Xu Y, Shen Q Front Cardiovasc Med. 2024; 11:1411621.

PMID: 39660120 PMC: 11628502. DOI: 10.3389/fcvm.2024.1411621.

Circular RNAs in coronary heart disease: From molecular mechanism to promising clinical application (Review).

Fan Z, Yuan X, Yuan Y Int J Mol Med. 2024; 55(1).

PMID: 39513584 PMC: 11573316. DOI: 10.3892/ijmm.2024.5452.

References

Shan S, Fang L, Shatseva T, Rutnam Z, Yang X, Du W . Mature miR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7 and vimentin in different signal pathways. J Cell Sci. 2013; 126(Pt 6):1517-30. DOI: 10.1242/jcs.122895. View

Du W, Liu F, Shan S, Ma X, Gupta S, Jin T . Inhibition of Dexamethasone-induced Fatty Liver Development by Reducing miR-17-5p Levels. Mol Ther. 2015; 23(7):1222-1233. PMC: 4817789. DOI: 10.1038/mt.2015.64. View

Jeck W, Sharpless N . Detecting and characterizing circular RNAs. Nat Biotechnol. 2014; 32(5):453-61. PMC: 4121655. DOI: 10.1038/nbt.2890. View

Zhang Y, Zhang X, Chen T, Xiang J, Yin Q, Xing Y . Circular intronic long noncoding RNAs. Mol Cell. 2013; 51(6):792-806. DOI: 10.1016/j.molcel.2013.08.017. View

Lee J, Kang B, Jang H, Kim T, Choi J, Kwak S . AKT phosphorylates H3-threonine 45 to facilitate termination of gene transcription in response to DNA damage. Nucleic Acids Res. 2015; 43(9):4505-16. PMC: 4482061. DOI: 10.1093/nar/gkv176. View

Holdt L, Stahringer A, Sass K, Pichler G, Kulak N, Wilfert W . Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun. 2016; 7:12429. PMC: 4992165. DOI: 10.1038/ncomms12429. View

Kuehnert J, Sommer G, Zierk A, Fedarovich A, Brock A, Fedarovich D . Novel RNA chaperone domain of RNA-binding protein La is regulated by AKT phosphorylation. Nucleic Acids Res. 2014; 43(1):581-94. PMC: 4288197. DOI: 10.1093/nar/gku1309. View

Yang B, Cao L, Kiani C, Lee V, Zhang Y, Adams M . Tandem repeats are involved in G1 domain inhibition of versican expression and secretion and the G3 domain enhances glycosaminoglycan modification and product secretion via the complement-binding protein-like motif. J Biol Chem. 2000; 275(28):21255-61. DOI: 10.1074/jbc.M001443200. View

Graham E, Balla C, Franchino H, Melman Y, Monte F, Das S . Isolation, culture, and functional characterization of adult mouse cardiomyoctyes. J Vis Exp. 2013; (79):e50289. PMC: 3935735. DOI: 10.3791/50289. View

10.

Lin H, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan C . Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nat Cell Biol. 2009; 11(4):420-32. PMC: 2830812. DOI: 10.1038/ncb1849. View

11.

Rutnam Z, Du W, Yang W, Yang X, Yang B . The pseudogene TUSC2P promotes TUSC2 function by binding multiple microRNAs. Nat Commun. 2014; 5:2914. PMC: 3896787. DOI: 10.1038/ncomms3914. View

12.

Zhang F, Chen M, Shan Q, Zou J, Chen C, Yang B . Hypoxia reoxygenation induces premature senescence in neonatal SD rat cardiomyocytes. Acta Pharmacol Sin. 2006; 28(1):44-51. DOI: 10.1111/j.1745-7254.2007.00488.x. View

13.

Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A . Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013; 495(7441):333-8. DOI: 10.1038/nature11928. View

14.

Tang X, Jang S, Wang X, Liu Z, Bahr S, Sun S . Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation. Nat Cell Biol. 2007; 9(10):1199-207. DOI: 10.1038/ncb1641. View

15.

Couderc C, Boin A, Fuhrmann L, Vincent-Salomon A, Mandati V, Kieffer Y . AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin. Neoplasia. 2016; 18(1):10-24. PMC: 4735628. DOI: 10.1016/j.neo.2015.11.010. View

16.

Khan M, Reckman Y, Aufiero S, van den Hoogenhof M, van der Made I, Beqqali A . RBM20 Regulates Circular RNA Production From the Titin Gene. Circ Res. 2016; 119(9):996-1003. DOI: 10.1161/CIRCRESAHA.116.309568. View

17.

Ehler E, Moore-Morris T, Lange S . Isolation and culture of neonatal mouse cardiomyocytes. J Vis Exp. 2013; (79). PMC: 3857885. DOI: 10.3791/50154. View

18.

Minamino T, Komuro I . Vascular cell senescence: contribution to atherosclerosis. Circ Res. 2007; 100(1):15-26. DOI: 10.1161/01.RES.0000256837.40544.4a. View

19.

Li Z, Huang C, Bao C, Chen L, Lin M, Wang X . Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015; 22(3):256-64. DOI: 10.1038/nsmb.2959. View

20.

Pekarsky Y, Koval A, Hallas C, Bichi R, Tresini M, Malstrom S . Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. Proc Natl Acad Sci U S A. 2000; 97(7):3028-33. PMC: 16186. DOI: 10.1073/pnas.97.7.3028. View