Intracellular Calcium Regulates Nonsense-Mediated mRNA Decay
| Autor: | Jayne Marasa, David Piwnica-Worms, Robert W. Mercer, Patrick Nugent, Zhongsheng You, Andrew Nickless, Erin Jackson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Digoxin
ATPase Nonsense-mediated decay Regulator chemistry.chemical_element Calcium Endoplasmic Reticulum General Biochemistry Genetics and Molecular Biology Calcium in biology Article Cell Line Cardiac Glycosides Genes Reporter Humans RNA Messenger Ouabain Calcium metabolism biology Endoplasmic reticulum Cell Membrane General Medicine 3. Good health Cell biology High-Throughput Screening Assays Nonsense Mediated mRNA Decay chemistry Biochemistry Cell culture Luminescent Measurements biology.protein Sodium-Potassium-Exchanging ATPase |
| Zdroj: | Nature medicine |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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