Signal transduction pathways leading to increased eIF4E phosphorylation caused by oxidative stress.
Phosphorylation of eIF4E is associated with increased activity of the translational machinery. Oxidative stress of resident vascular cells and macrophages potently enhances eIF4E phosphorylation. Oxidative stress activates numerous intracellular signaling pathways, including MAP-family kinase pathways and pathways leading to S6 kinase activation. The activation of MAP-family kinase pathways leads to the activation of Mnk and hence eIF4E phosphorylation, whereas the S6 kinase pathway is not involved, based on insensitivity to its inhibitors rapamycin and wortmannin. Ca-dependent pathways have been implicated in eIF4E phosphorylation, but the oxidative stress response pathway targeting eIF4E does not appear to require their participation. The results suggest that the potent activation of ERK and p38 protein kinases is sufficient to account for the enhanced eIF4E phosphorylation. Either is independently sufficient to effect the change, as neither PD098059 (Erk pathway inhibitor) nor SB202190 (p38 pathway inhibitor) alone can block the response, but when combined the response is almost completely abrogated. Mnk activation by oxidative stress leading to enhanced eIF4E phosphorylation may play a role in promoting stress-induced hyperproliferative diseases, such as smooth muscle cell proliferation and hypertrophy in cardiovascular disease, as the synthesis of several key regulators of cell growth has been shown to be held in check by moderation of eIF4E activity.
Duncan
Roger F
RF
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA. rduncan@usc.edu
Peterson
Hazel
H
Sevanian
Alex
A
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099221:Protein Kinase C zeta
D039561:Eukaryotic Initiation Factor-4E; D048049:Extracellular Signal-Regulated MAP Kinases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta; C106281:Mknk1 protein, mouse