Journal
NATURE MEDICINE
Volume 20, Issue 8, Pages 961-966Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3620
Keywords
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Funding
- Molecular Imaging Center from the US National Institutes of Health
- University of Texas MD Anderson Cancer Center [P50 CA94056]
- Washington University Molecular Imaging Center
- US National Institutes of Health [R01GM098535]
- Interdisciplinary Research Initiative from the Children's Discovery Institute of Washington University [MC-II-2012-215]
- Siteman Cancer Center (Cancer Center from the US National Cancer Institute) [P30 CA91842]
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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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