The role of mitogen-activated protein kinase phosphatase-1 in oxidative damage-induced cell death.
Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a member of the MAPK phosphatase family that functions as a negative regulator of MAPK signaling. MKP-1 is induced by oxidative stress, but the role of its induction in cell death is not fully understood. Here, we show that hydrogen peroxide (H(2)O(2)) induces MKP-1 and activates MAPKs. Induction of MKP-1 by H(2)O(2) correlated with inactivation of p38 and c-Jun-NH(2)-kinase (JNK). Overexpression of MKP-1 increased cell resistance to H(2)O(2)-induced death. Furthermore, we show by small interfering RNA silencing that down-regulation of MKP-1 increases phosphorylated p38 and JNK and subsequent cell death induced by H(2)O(2). More importantly, primary embryonic fibroblasts from mice lacking MKP-1 had a higher level of phosphorylated p38 and JNK and were more sensitive to H(2)O(2)-induced cell death compared with corresponding cells with MKP-1, indicating that p38 and JNK pathways may play important roles in H(2)O(2)-mediated cell death. Thus, these results suggest that activation of MKP-1 is a survival mechanism against oxidative damage.
Zhou
Jun-Ying
JY
Program in Molecular Biology and Human Genetics, Karmanos Cancer Institute, Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Liu
Yusen
Y
Wu
Gen Sheng
GS
D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D004790:Enzyme Induction / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases