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      The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: Complement of the canonical p53/p21 pathway

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          Abstract

          Aging is a multifactorial process characterized by the progressive deterioration of physiological functions. Among the multiple molecular mechanisms, microRNAs (miRNAs) have increasingly been implicated in the regulation of Aging process. However, the contribution of miRNAs to physiological Aging and the underlying mechanisms remain elusive. We herein performed high‐throughput analysis using miRNA and mRNA microarray in the physiological Aging mouse, attempted to deepen into the understanding of the effects of miRNAs on Aging process at the “network” level. The data showed that various p53 responsive miRNAs, including miR‐124, miR‐34a and miR‐29a/b/c, were up‐regulated in Aging mouse compared with that in Young mouse. Further investigation unraveled that similar as miR‐34a and miR‐29, miR‐124 significantly promoted cellular senescence. As expected, mRNA microarray and gene co‐expression network analysis unveiled that the most down‐regulated mRNAs were enriched in the regulatory pathways of cell proliferation. Fascinatingly, among these down‐regulated mRNAs, Ccna2 stood out as a common target of several p53 responsive miRNAs (miR‐124 and miR‐29), which functioned as the antagonist of p21 in cell cycle regulation. Silencing of Ccna2 remarkably triggered the cellular senescence, while Ccna2 overexpression delayed cellular senescence and significantly reversed the senescence‐induction effect of miR‐124 and miR‐29. Moreover, these p53 responsive miRNAs were significantly up‐regulated during the senescence process of p21‐deficient cells; overexpression of p53 responsive miRNAs or knockdown of Ccna2 evidently accelerated the cellular senescence in the absence of p21. Taken together, our data suggested that the p53/miRNAs/Ccna2 pathway might serve as a novel senescence modulator independent of p53/p21 pathway.

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          Senescence and aging: the critical roles of p53.

          p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis and cellular stress responses. However, besides inducing cell growth arrest and apoptosis, p53 activation also modulates cellular senescence and organismal aging. Senescence is an irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent by its expression and cellular context. In this review, we focus on the recent advances on the contribution of p53 to cellular senescence and its implication for cancer therapy, and we will discuss p53's impact on animal lifespan. Moreover, we describe p53-mediated regulation of several physiological pathways that could mediate its role in both senescence and aging.
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            MicroRNA-34a regulates cardiac ageing and function.

            Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.
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              MicroRNAs and their roles in aging.

              MicroRNAs (miRNAs) are a class of short non-coding RNAs that bind mRNAs through partial base-pair complementarity with their target genes, resulting in post-transcriptional repression of gene expression. The role of miRNAs in controlling aging processes has been uncovered recently with the discovery of miRNAs that regulate lifespan in the nematode Caenorhabditis elegans through insulin and insulin-like growth factor-1 signaling and DNA damage checkpoint factors. Furthermore, numerous miRNAs are differentially expressed during aging in C. elegans, but the specific functions of many of these miRNAs are still unknown. Recently, various miRNAs have been identified that are up- or down-regulated during mammalian aging by comparing their tissue-specific expression in younger and older mice. In addition, many miRNAs have been implicated in governing senescence in a variety of human cell lines, and the precise functions of some of these miRNAs in regulating cellular senescence have helped to elucidate mechanisms underlying aging. In this Commentary, we review the various regulatory roles of miRNAs during aging processes. We highlight how certain miRNAs can regulate aging on the level of organism lifespan, tissue aging or cellular senescence. Finally, we discuss future approaches that might be used to investigate the mechanisms by which miRNAs govern aging processes.
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                Author and article information

                Contributors
                xgliu64@126.com
                Journal
                Aging Cell
                Aging Cell
                10.1111/(ISSN)1474-9726
                ACEL
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                1474-9718
                1474-9726
                07 March 2019
                June 2019
                : 18
                : 3 ( doiID: 10.1111/acel.2019.18.issue-3 )
                : e12918
                Affiliations
                [ 1 ] Institute of Aging Research Guangdong Medical University Dongguan China
                [ 2 ] Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics Guangdong Medical University Dongguan China
                [ 3 ] The Scientific Research Center of Dongguan Guangdong Medical University Dongguan China
                [ 4 ] Department of Oncology Dongguan People's Hospital Dongguan China
                [ 5 ] Institute of Biochemistry & Molecular Biology Guangdong Medical University Zhanjiang China
                Author notes
                [*] [* ] Correspondence

                Xinguang Liu, Institute of Aging Research, Guangdong Medical University, Dongguan, China.

                Email: xgliu64@ 123456126.com

                Article
                ACEL12918
                10.1111/acel.12918
                6516184
                30848072
                bb1fa619-9d1d-41ff-87db-0ba88a09aa5d
                © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 01 May 2018
                : 27 October 2018
                : 25 November 2018
                Page count
                Figures: 6, Tables: 0, Pages: 14, Words: 7700
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 31600976
                Award ID: 81671399
                Award ID: 81170327
                Funded by: Natural Science Foundation of Guangdong Province
                Award ID: 2016A030313684
                Award ID: 9252402301000002
                Funded by: Innovation Team Construction Projects in Ordinary University of Guangdong Province
                Award ID: 2015KCXTD022
                Funded by: Unique Innovative Projects in Ordinary University of Guangdong Province
                Award ID: 2015KTSCX049
                Funded by: Science & Technology Innovation Fund of Guangdong Medical University
                Award ID: STIF201102
                Funded by: “Climbing” Program of Guangdong Province
                Award ID: pdjh2016b0219
                Award ID: pdjhb0223
                Funded by: Dongguan International Science & Technology Cooperation
                Award ID: 201650812001
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                acel12918
                June 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:14.05.2019

                Cell biology
                aging,ccna2,cellular senescence,mirna,p53
                Cell biology
                aging, ccna2, cellular senescence, mirna, p53

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