Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10738859 | Free Radical Biology and Medicine | 2005 | 13 Pages |
Abstract
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.
Keywords
DPIMAP kinase kinase kinasePDK1PP2PKRphorbol 12-myristate 13-acetateRTKHCRImmunoprecipitateGCsEBSSBSOS6KTSCPI3KMBPTORFBSDMEMEGFphosphoinositide-dependent protein kinase 1eIFPMAbuthionine sulfoximineOxidative stressFree radicalsfetal bovine serumepidermal growth factorInitiation factorsEukaryotic Initiation FactorPhosphatidylinositol 3-kinasePhosphorylationDulbecco's Modified Essential MediumSignal transductiontarget of rapamycineIF4E-binding proteinribosomal protein S6 kinaseMyelin basic proteinPERKTuberous sclerosis complexReceptor Tyrosine Kinase
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Authors
Roger F. Duncan, Hazel Peterson, Alex Sevanian,