Intracellular calcium regulates nonsense-mediated mRNA decay.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
    • Publication Information:
      Publication: New York Ny : Nature Publishing Company
      Original Publication: New York, NY : Nature Pub. Co., [1995-
    • Subject Terms:
      Calcium/*metabolism ; Nonsense Mediated mRNA Decay/*genetics ; Sodium-Potassium-Exchanging ATPase/*antagonists & inhibitors; Cardiac Glycosides/metabolism ; Cell Line ; Cell Membrane/enzymology ; Digoxin/metabolism ; Endoplasmic Reticulum/metabolism ; Genes, Reporter ; High-Throughput Screening Assays/methods ; Humans ; Luminescent Measurements ; Ouabain/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
    • Abstract:
      The nonsense-mediated mRNA decay (NMD) pathway selectively eliminates aberrant transcripts containing premature translation termination codons 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 a target for therapeutic intervention. Here, we have developed a new 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 sodium-potassium ATPase on the plasma membrane and subsequent elevation of intracellular calcium levels. Induction of calcium release from the endoplasmic reticulum also leads to inhibition of NMD. Thus, this study reveals intracellular calcium as a key regulator of NMD and has implications for exploiting NMD in the treatment of disease.
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    • Grant Information:
      P50 CA094056 United States CA NCI NIH HHS; T32 CA113275 United States CA NCI NIH HHS; R01 GM098535 United States GM NIGMS NIH HHS; P30 CA91842 United States CA NCI NIH HHS; P50 CA94056 United States CA NCI NIH HHS; R01GM098535 United States GM NIGMS NIH HHS
    • Accession Number:
      0 (Cardiac Glycosides)
      0 (RNA, Messenger)
      5ACL011P69 (Ouabain)
      73K4184T59 (Digoxin)
      EC 7.2.2.13 (Sodium-Potassium-Exchanging ATPase)
      SY7Q814VUP (Calcium)
    • Publication Date:
      Date Created: 20140728 Date Completed: 20141010 Latest Revision: 20240620
    • Publication Date:
      20240620
    • Accession Number:
      PMC4126864
    • Accession Number:
      10.1038/nm.3620
    • Accession Number:
      25064126