Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH2-terminal kinase-mediated apoptosis via NF-kappaB regulation.
The mechanism regulating radiation-induced anti-apoptotic response, a limiting factor in improving cell radiosensitivity, remains elusive. Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 is the major member of MKPs that dephosphorylates and inactivates MAPK. Here we provide the evidence that MKP-1 was negatively bridging between NF-kappaB-mediated prosurvival pathway and c-Jun N-terminal kinase (JNK)-mediated proapoptotic response. MKP-1 was induced by gamma-radiation and repressed radiation-induced pro-apoptotic status. NF-kappaB RelA/p50 heterodimer was recruited to MKP-1 gene promoter to induce MKP-1 transcription. Deletion of the NF-kappaB-binding site or inactivation of NF-kappaB by its small interfering RNA significantly decreased the radiation-induced MKP-1 promoter activity. In addition, MKP-1-deficient mouse embryonic fibroblasts exhibited a prolonged activation of JNK but not p38 or extracellular signal-regulated kinase subfamilies of MAPKs. The prolonged activation of JNK was not induced by treatment with tumor necrosis factor alpha or interleukin-6, and inactivation of JNK but not p38 or ERK abolished radiation-induced proapoptotic status, indicating that JNK is specifically inhibited by radiation-induced MKP-1. Three MKP-1 wild type human tumor cell lines treated with MKP-1 small interfering RNA showed an increased proapoptotic response that can be rescued by overexpression of wild type mouse MKP-1. Together, these results suggest that MKP-1 is a NF-kappaB-mediated prosurvival effector in attenuating JNK-mediated pro-apoptotic response; NF-kappaB/MKP-1-mediated negative JNK regulation represents a potential therapeutic target for adjusting cell radiosensitivity.
Division of Molecular Radiobiology, Purdue University School of Health Sciences, 550 Stadium Mall Drive, West Lafayette, IN 47907, USA.
Zhaoqing
Z
Wang
Ning
N
Cao
Danupon
D
Nantajit
Ming
M
Fan
Yusen
Y
Liu
Jian Jian
JJ
Li
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D005720:Gamma Rays; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016328:NF-kappa B; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases