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Hyperglycemia mediates a shift from cap‐dependent to capindependent mRNA translation through a 4E‐BP1 dependent mechanism

In both liver of diabetic mice and cells in culture exposed to hyperglycemic conditions 4E‐BP1 is modified by OGlcNAcylation concomitant with enhanced expression and interaction with the mRNA cap‐binding protein eIF4E. Interaction of 4E‐BP1 with eIF4E plays a major role in the regulation of gene expression by controlling the selection of mRNAs for translation. In the present study, we evaluated the hypothesis that hyperglycemia alters the profile of mRNAs selected for translation. Using pulsed stable isotope labeling by amino acids in cell culture (pSILAC) we identified proteins with altered rates of synthesis upon exposure to medium containing 25 compared to 5 mM glucose. The mRNAs encoding proteins whose synthesis was most enhanced contained longer, more complex 5′‐UTRs, suggesting hyperglycemia favors the translation of mRNAs with more structured 5′‐UTRs, including those containing internal ribosome entry sites. Using a bicistronic luciferase reporter assay, the high glucose condition also caused a repression of cap‐dependent and enhancement of cap‐independent mRNA translation. Notably, the glucose‐induced shift from cap‐dependent to cap‐independent mRNA translation did not occur in cells lacking 4E‐BP1. (Supported by NIH grant 13499 (LSJ) and an NIH Postdoctoral Fellowship (MDD))