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Nitrosative Stress Triggers Inhibition of DNA Synthesis and Translational Suppression of Positive Cell Cycle Regulators

Nitrosative stress or aberrant accumulation of intracellular nitroso‐species has recently emerged as a candidate regulator of cellular processes such as transcription, cell signaling, and apoptosis. We report herein that nitrosative stress, generated by expression of human inducible nitric oxide synthase (hiNOS) or by treatment with the cell‐permeable S‐nitrosating agent S‐nitrosocysteine ethyl ester (SNCEE), induced hyperphosphorylation of the translational regulator eIF‐2α at the inhibitory residue Ser51, repression of protein translation as measured by 35S‐incorporation, and inhibition of DNA synthesis as measured by bromodeoxyuridine incorporation. As inhibition of protein translation would initially alter the levels of rapidly turned‐over proteins, we hypothesized that loss of one or more short half‐life cell cycle proteins was responsible for the observed halt of DNA synthesis under nitrosative stress. Indeed, we observed decreased expression of the Cdc25A protein, which drives progression through S‐phase by activating cyclin‐dependent kinase 2 complexes, as well as decreased protein levels of two other cell cycle proteins, c‐Myc and Cyclin D1, with kinetics that precede DNA synthesis inhibition. Together, these results suggest that nitrosative stress may initiate a program to stop progression through S‐phase until perturbation of the intracellular redox status has been resolved.