N-acetyl-cysteine abolishes hydrogen peroxide-induced modification of eukaryotic initiation factor 4F activity via distinct signalling pathways.
During the oxidative stress generated by hydrogen peroxide (H2O2) in nerve growth factor (NGF)-differentiated PC12 cells, eIF4E binding protein (4E-BP1) and initiation factor 4E (eIF4E) phosphorylated levels decrease significantly, and an enhancement of the association of 4E-BP1 to eIF4E, which in turn decreases eIF4F formation is observed. The treatment with N-acetyl-cysteine (NAC) completely abolishes the H2O2-induced decrease in eIF4E phosphorylated levels, whereas the decrease in 4E-BP1 phosphorylated levels and eIF4F activity inhibition are significantly but not fully reversed. Rapamycin, the mammalian target of rapamycin (FRAP/mTOR) inhibitor, prevents the effect of NAC on H2O2-induced eIF4F complex formation inhibition. Besides the inhibitor induces a similar decrease in 4E-BP1 phosphorylated levels to that promote by H2O2. However, rapamycin has no effect on the NAC-induced recovery in phosphorylated eIF4E levels. Neither the MAP kinase inhibitors, PD98056 and SB203580, or the protein phosphatase 2A inhibitor, okadaic acid, mimic NAC effect on the H2O2-induced eIF4E dephosphorylation. Altogether our findings suggest that the effects caused by oxidative stress on eIF4s factors depends on two MAP kinase-independent signal transduction pathways, being at least one of them rapamycin-dependent.
O'Loghlen
A
A
Servicio de Bioquímica, Departamento de Investigación, Hospital Ramón y Cajal, Ctra. Colmenar Km. 9, 28034 Madrid, Spain.
Pérez-Morgado
M I
MI
Salinas
M
M
Martín
M E
ME
D000111:Acetylcysteine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D039562:Eukaryotic Initiation Factor-4F / Q000187:drug effects / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D019319:Okadaic Acid / Q000494:pharmacology; D016716:PC12 Cells; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011725:Pyridines; D019319:Okadaic Acid; D006861:Hydrogen Peroxide; C093642:SB 203580; D020123:Sirolimus; D000111:Acetylcysteine