Cellular defense against H2O2-induced apoptosis via map kinase-MKP-1 pathway

TY - JOUR

T1 - Cellular defense against H2O2-induced apoptosis via map kinase-MKP-1 pathway

AU - Xu, Q H

AU - Konta, T

AU - Nakayama, K J

AU - Furusu, A

AU - Moreno-Manzano, V

AU - Lucio-Cazana, J

AU - Ishikawa, Y

AU - Fine, L G

AU - Yao, J

AU - Kitamura, M

PY - 2004/4/15

Y1 - 2004/4/15

N2 - Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is an oxidative stress-inducible gene. In this study. we investigated signaling pathways involved in oxidative stress-induced MKP-1 expression and its role in apoptosis of rat mesangial cells. Northern and Western blot analyses showed that H2O2 induced expression of MKP-1 mRNA and protein in a dose-dependent manner, without affecting the stability of the transcript. H2O2 induced phosphorylation of extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun N-terminal kinase and consequently activated activator protein 1 (AP-1). Selective inhibitors of individual MAP kinases or a dominant-negative mutant of c-jun significantly suppressed the expression of MKP-1 by H2O2. Inhibition of MKP-1 by a protein tyrosine phosphatase inhibitor (vanadate) enhanced H2O2-triggered apoptosis. Consistently, transfection with a wild-type MKP-1, but not its catalytically inactive mutant MKP-ICS, attenuated H2O2-induced apoptosis. These data elucidate, for the first time, that induction of MKP-1 by H2O2 is mediated by the MAP kinase-AP-1 pathway and that the induced MKP-1 is involved in cellular defense against oxidative stress-induced apoptosis of mesangial cells. (C) 2004 Elsevier Inc. All rights reserved

AB - Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is an oxidative stress-inducible gene. In this study. we investigated signaling pathways involved in oxidative stress-induced MKP-1 expression and its role in apoptosis of rat mesangial cells. Northern and Western blot analyses showed that H2O2 induced expression of MKP-1 mRNA and protein in a dose-dependent manner, without affecting the stability of the transcript. H2O2 induced phosphorylation of extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun N-terminal kinase and consequently activated activator protein 1 (AP-1). Selective inhibitors of individual MAP kinases or a dominant-negative mutant of c-jun significantly suppressed the expression of MKP-1 by H2O2. Inhibition of MKP-1 by a protein tyrosine phosphatase inhibitor (vanadate) enhanced H2O2-triggered apoptosis. Consistently, transfection with a wild-type MKP-1, but not its catalytically inactive mutant MKP-ICS, attenuated H2O2-induced apoptosis. These data elucidate, for the first time, that induction of MKP-1 by H2O2 is mediated by the MAP kinase-AP-1 pathway and that the induced MKP-1 is involved in cellular defense against oxidative stress-induced apoptosis of mesangial cells. (C) 2004 Elsevier Inc. All rights reserved

U2 - 10.1016/j.freeradbiomed.2004.01.009

DO - 10.1016/j.freeradbiomed.2004.01.009

M3 - Article

VL - 36

SP - 985

EP - 993

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

IS - 8

ER -