Washington University in St. Louis

Congratulations to Dr. Zhongsheng You on his new publication in Nature Medicine!

You Lab findings reported in Nature Medicine.

Dr. You and his team have uncovered a novel link between intracellular calcium and the nonsense-mediated mRNA decay (NMD) surveillance pathway.  Regulation of NMD by calcium may be important for many biological processes such as development, neuronal function, immune activation and cell proliferation.  Regulation of the NMD pathway by manipulation of intracellular calcium levels may yield new therapeutic strategies for certain genetic diseases and cancer.

Nickless A, Jackson E, Marasa J, Nugent P, Mercer RW, Piwnica-Worms D, and You Z.  “Intracellular Calcium Regulates Nonsense-Mediated mRNA Decay.”   [Published online July 27, 2014]

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.

*To access the complete journal article, click here.

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