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J. Biol. Chem., Vol. 283, Issue 30, 21011-21023, July 25, 2008

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Mitogen-activated Protein Kinase Phosphatase-1 Represses c-Jun NH₂-terminal Kinase-mediated Apoptosis via NF-B Regulation^*

Zhaoqing Wang, Ning Cao, Danupon Nantajit, Ming Fan, Yusen Liu, and Jian Jian Li¹

From the Division of Molecular Radiobiology, Purdue University School of Health Sciences, West Lafayette, Indiana 47907 and the Children's Research Institute, Department of Pediatrics, Ohio State University, Columbus, Ohio 43205

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-B-mediated prosurvival pathway and c-Jun N-terminal kinase (JNK)-mediated proapoptotic response. MKP-1 was induced by -radiation and repressed radiation-induced pro-apoptotic status. NF-B RelA/p50 heterodimer was recruited to MKP-1 gene promoter to induce MKP-1 transcription. Deletion of the NF-B-binding site or inactivation of NF-B 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 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-B-mediated prosurvival effector in attenuating JNK-mediated pro-apoptotic response; NF-B/MKP-1-mediated negative JNK regulation represents a potential therapeutic target for adjusting cell radiosensitivity.

Received for publication, March 20, 2008 , and in revised form, May 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 101990 (to J. J. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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¹ To whom correspondence should be addressed: Rm. 1279 Civil Engineering Bldg., 550 Stadium Mall Dr., Purdue University, West Lafayette, IN 47907. Tel.: 765-496-6792; Fax: 765-496-1377; E-mail: jjli{at}purdue.edu.

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