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J. Biol. Chem., Vol. 275, Issue 22, 16993-16999, June 2, 2000

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Oxidant Stress Stimulates Phosphorylation of eIF4E without an Effect on Global Protein Synthesis in Smooth Muscle Cells
LACK OF EVIDENCE FOR A ROLE OF H₂O₂ IN ANGIOTENSIN II-INDUCED HYPERTROPHY^*

Gadiparthi N. Rao

From the Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston, Texas 77555

Reactive oxygen species (ROS) are implicated in the pathogenesis of several proliferative diseases, including atherosclerosis and cancer. Eukaryotic translation initiation factor 4E (eIF4E) plays an important role in cell proliferation and differentiation. To gain insight into molecular mechanisms by which ROS influence the pathogenesis of these diseases, I have studied the effect of H₂O₂, a ROS, on eIF4E phosphorylation. H₂O₂ induced eIF4E phosphorylation in a dose- and time-dependent manner in growth-arrested smooth muscle cells (SMC). H₂O₂-induced eIF4E phosphorylation occurred on serine residues. PD098059, a specific inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase inhibited ERK activities but had no significant effect on eIF4E phosphorylation induced by H₂O₂. Similarly, SB203580, a specific inhibitor of p38 MAPK, although inhibiting H₂O₂-induced p38 MAPK activity, had no effect on H₂O₂-induced eIF4E phosphorylation. Calphostin C, a specific inhibitor of protein kinase C, also had no effect on H₂O₂-induced eIF4E phosphorylation. In contrast, trifluoperazine, an antagonist of calcium/calmodulin kinases, completely blocked H₂O₂-induced eIF4E phosphorylation. In addition, intracellular and extracellular Ca²⁺ chelators significantly inhibited H₂O₂-induced eIF4E phosphorylation. Despite its ability to induce eIF4E phosphorylation, H₂O₂ had no significant effect on protein levels and new protein synthesis as compared with control. In contrast, it induced the expression of c-Fos, c-Jun, and HSP70 in a time-dependent manner in SMC. Together, these results suggest that H₂O₂, a ROS and a cellular oxidant, induces eIF4E phosphorylation in a manner that is dependent on Ca²⁺ and Ca²⁺/calmodulin kinases and independent of ERKs, p38 MAPK, and protein kinase C. These results also suggest that enhanced eIF4E phosphorylation by H₂O₂ appears to be an important event in SMC in response to oxidant stress and that eIF4E phosphorylation may be associated with the translation of a small subset of mRNAs such as c-fos, c-jun, and HSP70 gene mRNAs, whose products may have a critical role in cell survival.

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