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      Intracellular Calcium Regulates Nonsense-Mediated mRNA Decay

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          Abstract

          The nonsense-mediated mRNA decay (NMD) pathway selectively eliminates aberrant transcripts containing premature translation termination codons (PTCs) and regulates the levels of a number of physiological mRNAs. NMD modulates the clinical outcome of a variety of human diseases, including cancer and many genetic disorders, and may represent an important target for therapeutic intervention. Here we have developed a novel multicolored, bioluminescence-based reporter system that can specifically and effectively assay NMD in live human cells. Using this reporter system, we conducted a robust high-throughput small-molecule screen in human cells and, unpredictably, identified a group of cardiac glycosides including ouabain and digoxin as potent inhibitors of NMD. Cardiac glycoside-mediated effects on NMD are dependent on binding and inhibiting the Na +/K +-ATPase on the plasma membrane and subsequent elevation of intracellular calcium levels. Induction of calcium release from endoplasmic reticulum also leads to inhibition of NMD. Thus, this study reveals intracellular calcium as a key regulator of NMD and has important implications for exploiting NMD in the treatment of disease.

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          Most cited references 34

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          NMD: a multifaceted response to premature translational termination.

          Although most mRNA molecules derived from protein-coding genes are destined to be translated into functional polypeptides, some are eliminated by cellular quality control pathways that collectively perform the task of mRNA surveillance. In the nonsense-mediated decay (NMD) pathway premature translation termination promotes the recruitment of a set of factors that destabilize a targeted mRNA. The same factors also seem to have key roles in repressing the translation of the mRNA, dissociating its terminating ribosome and messenger ribonucleoproteins (mRNPs), promoting the degradation of its truncated polypeptide product and possibly even feeding back to the site of transcription to interfere with splicing of the primary transcript.
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            Regulation of cytoplasmic mRNA decay.

            Discoveries made over the past 20 years highlight the importance of mRNA decay as a means of modulating gene expression and thereby protein production. Up until recently, studies largely focused on identifying cis-acting sequences that serve as mRNA stability or instability elements, the proteins that bind these elements, how the process of translation influences mRNA decay and the ribonucleases that catalyse decay. Now, current studies have begun to elucidate how the decay process is regulated. This Review examines our current understanding of how mammalian cell mRNA decay is controlled by different signalling pathways and lays out a framework for future research.
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              Nonsense-mediated decay approaches the clinic.

              Nonsense-mediated decay (NMD) eliminates mRNAs containing premature termination codons and thus helps limit the synthesis of abnormal proteins. New results uncover a broader role of NMD as a pathway that also affects the expression of wild-type genes and alternative-splice products. Because the mechanisms by which NMD operates have received much attention, we discuss here the emerging awareness of the impact of NMD on the manifestation of human genetic diseases. We explore how an understanding of NMD accounts for phenotypic differences in diseases caused by premature termination codons. Specifically, we consider how the protective function of NMD sometimes benefits heterozygous carriers and, in contrast, sometimes contributes to a clinical picture of protein deficiency by inhibiting expression of partially functional proteins. Potential 'NMD therapeutics' will therefore need to strike a balance between the general physiological benefits of NMD and its detrimental effects in cases of specific genetic mutations.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                12 April 2014
                27 July 2014
                August 2014
                01 February 2015
                : 20
                : 8
                : 961-966
                Affiliations
                [1 ]Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
                [2 ]BRIGHT Institute, Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110
                [3 ]Department of Cancer Systems Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
                Author notes
                [* ]Corresponding authors: Zhongsheng You, PhD, Washington University School of Medicine, Campus Box 8228, 660 S. Euclid Ave., St. Louis, 63110, zyou@ 123456wustl.edu , Phone: 314-362-9893, Fax: 314-362-7463, David Piwnica-Worms, MD, PhD, The University of Texas M.D. Anderson Cancer Center, 1400 Pressler Street, Unit 1479, FCT16.5098, Houston, Texas 77030, dpiwnica-worms@ 123456mdanderson.org , Phone: 713-745-0850, Fax: 713-745-7540
                Article
                NIHMS569922
                10.1038/nm.3620
                4126864
                25064126
                Categories
                Article

                Medicine

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