Exposure of PC12 cells to 100 muM peroxynitrite promotes phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) sensitive to PD98059 or U0126. At higher concentrations, however, ERK1/2 phosphorylation was prevented by U0126 and increased by PD98059 via a U0126-sensitive mechanism. PD98059, unlike U0126, enhanced the peroxynitrite-dependent formation of reactive oxygen species (ROS). These results, along with others obtained using respiratory chain inhibitors and respiration-deficient cells, lead to the conclusion that PD98059, while effectively inhibiting the peroxynitrite-induced Raf/MEK signaling leading to ERK1/2 phosphorylation, promotes an enforced mitochondrial formation of ROS inducing ERK1/2 phosphorylation via a Raf-1-independent/MEK-dependent mechanism. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
THE RAF/MEK INHIBITOR PD98059 ENHANCES ERK1/2 PHOSPHORYLATION MEDIATED BY PEROXYNITRITE VIA ENFORCED MITOCHONDRIAL FORMATION OF REACTIVE OXYGEN SPECIES.
CERIONI, LIANA;PALOMBA, LETIZIA;CANTONI, ORAZIO
2003
Abstract
Exposure of PC12 cells to 100 muM peroxynitrite promotes phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) sensitive to PD98059 or U0126. At higher concentrations, however, ERK1/2 phosphorylation was prevented by U0126 and increased by PD98059 via a U0126-sensitive mechanism. PD98059, unlike U0126, enhanced the peroxynitrite-dependent formation of reactive oxygen species (ROS). These results, along with others obtained using respiratory chain inhibitors and respiration-deficient cells, lead to the conclusion that PD98059, while effectively inhibiting the peroxynitrite-induced Raf/MEK signaling leading to ERK1/2 phosphorylation, promotes an enforced mitochondrial formation of ROS inducing ERK1/2 phosphorylation via a Raf-1-independent/MEK-dependent mechanism. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
