Mitochondrial H2O2 limits U937 cell survival to peroxynitrite by promoting ERK1/2 dephosphorylation.
Sequential activation of cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO), critically regulated by extracellular signal-regulated kinase 1 and 2 (ERK1/2)-dependent phosphorylation, mediates U937 cell survival to peroxynitrite. In contrast, a limiting factor is represented by the parallel mitochondrial formation of H2O2 leading to suppression of the survival signaling. We now report that the inhibitory effects of H2O2 are at the level of ERK1/2 phosphorylation and involve activation of orthovanadate-sensitive phosphotyrosine protein phosphatase(s). Under these conditions, the otherwise stimulatory effects of peroxynitrite on ERK1/2 phosphorylation are concealed by phosphatase-dependent dephosphorylation and the activities of cPLA2 and 5-LO are significantly reduced or suppressed, respectively. The ensuing inhibition of downstream events preventing mitochondrial permeability transition rapidly leads these cells to death. Thus, endogenous H2O2 limits U937 cell survival to peroxynitrite via activation of phosphotyrosine protein phosphatase(s) promoting upstream inhibition of the survival signaling critically regulated by the extent of ERK1/2 phosphorylation.
Cerioni
Liana
L
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino "Carlo Bo", Italy.
Cantoni
Orazio
O
D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020298:U937 Cells; D014638:Vanadates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D030421:Peroxynitrous Acid; D014638:Vanadates; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017027:Protein Tyrosine Phosphatases