Cellular defense against H2O2-induced apoptosis via MAP kinase-MKP-1 pathway.
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 H(2)O(2) induced expression of MKP-1 mRNA and protein in a dose-dependent manner, without affecting the stability of the transcript. H(2)O(2) 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 H(2)O(2). Inhibition of MKP-1 by a protein tyrosine phosphatase inhibitor (vanadate) enhanced H(2)O(2)-triggered apoptosis. Consistently, transfection with a wild-type MKP-1, but not its catalytically inactive mutant MKP-1CS, attenuated H(2)O(2)-induced apoptosis. These data elucidate, for the first time, that induction of MKP-1 by H(2)O(2) 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.
Xu
Qihe
Q
Department of Medicine, Royal Free and University College Medical School, University College London, London, England, United Kingdom.
Konta
Tsuneo
T
Nakayama
Kenji
K
Furusu
Akira
A
Moreno-Manzano
Victoria
V
Lucio-Cazana
Javier
J
Ishikawa
Yoshihisa
Y
Fine
Leon G
LG
Yao
Jian
J
Kitamura
Masanori
M
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals; D005920:Glomerular Mesangium / Q000473:pathology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005609:Free Radicals; D017874:Immediate-Early Proteins; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases