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      Regulatory non-coding RNA: new instruments in the orchestration of cell death

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          Abstract

          Non-coding RNA (ncRNA) comprises a substantial portion of primary transcripts that are generated by genomic transcription, but are not translated into protein. The possible functions of these once considered ‘junk' molecules have incited considerable interest and new insights have emerged. The two major members of ncRNAs, namely micro RNA (miRNA) and long non-coding RNA (lncRNA), have important regulatory roles in gene expression and many important physiological processes, which has recently been extended to programmed cell death. The previous paradigm of programmed cell death only by apoptosis has recently expanded to include modalities of regulated necrosis (RN), and particularly necroptosis. However, most research efforts in this field have been on protein regulators, leaving the role of ncRNAs largely unexplored. In this review, we discuss important findings concerning miRNAs and lncRNAs that modulate apoptosis and RN pathways, as well as the miRNA–lncRNA interactions that affect cell death regulation.

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          Most cited references131

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          Switching from repression to activation: microRNAs can up-regulate translation.

          AU-rich elements (AREs) and microRNA target sites are conserved sequences in messenger RNA (mRNA) 3' untranslated regions (3'UTRs) that control gene expression posttranscriptionally. Upon cell cycle arrest, the ARE in tumor necrosis factor-alpha (TNFalpha) mRNA is transformed into a translation activation signal, recruiting Argonaute (AGO) and fragile X mental retardation-related protein 1 (FXR1), factors associated with micro-ribonucleoproteins (microRNPs). We show that human microRNA miR369-3 directs association of these proteins with the AREs to activate translation. Furthermore, we document that two well-studied microRNAs-Let-7 and the synthetic microRNA miRcxcr4-likewise induce translation up-regulation of target mRNAs on cell cycle arrest, yet they repress translation in proliferating cells. Thus, activation is a common function of microRNPs on cell cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle.
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            Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.

            We report here the purification of the third protein factor, Apaf-3, that participates in caspase-3 activation in vitro. Apaf-3 was identified as a member of the caspase family, caspase-9. Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. Activated caspase-9 in turn cleaves and activates caspase-3. Depletion of caspase-9 from S-100 extracts diminished caspase-3 activation. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP.
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              Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.

              Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. Strikingly, Noxa bound only Mcl-1 and A1. In accord with their complementary binding, Bad and Noxa cooperated to induce potent killing. The results suggest that apoptosis relies on selective interactions between particular subsets of these proteins and that it should be feasible to discover BH3-mimetic drugs that inactivate specific prosurvival targets.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                August 2016
                11 August 2016
                1 August 2016
                : 7
                : 8
                : e2333
                Affiliations
                [1 ]Matthew Mailing Centre for Translational Transplantation Studies, Lawson Health Research Institute, London Health Sciences Centre, University of Western Ontario , London, Ontario, Canada
                [2 ]Department of Medicine, University of Western Ontario , London, Ontario, Canada
                [3 ]Department of Pathology, University of Western Ontario , London, Ontario, Canada
                [4 ]Key Laboratory of Kidney Diseases, Department of Pathology, Hebei Medical University , Shijiazhuang, China
                [5 ]Department of Oncology, Affiliated Hospital of Southwest Medical University , Luzhou, Sichuan, China
                [6 ]Department of Oncology and Immunotherapy, Hebei General Hospital , Shijiazhuang, China
                Author notes
                [* ]Matthew Mailing Centre for Translational Transplantation Studies, Lawson Health Research Institute, London Health Sciences Centre, University of Western Ontario, University Hospital , 339 Windermere Road, London, ON N6A 5A5, Canada. Tel: +519-663-3688, Fax: +519-663-2932;E-mail: jevnikar@ 123456uwo.ca
                [7]

                These authors contributed equally to this work.

                Article
                cddis2016210
                10.1038/cddis.2016.210
                5108314
                27512954
                f33115a9-328f-4866-8783-06f97478c681
                Copyright © 2016 The Author(s)

                Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 18 May 2016
                : 10 June 2016
                : 20 June 2016
                Categories
                Review

                Cell biology
                Cell biology

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