Mitogen-activated protein kinase phosphatase-1 represses c-Jun NH 2-terminal kinase-mediated apoptosis via NF-κB regulation

Zhaoqing Wang, Ning Cao, Danupon Nantajit, Ming Fan, Yusen Liu, Jian-Jian Li

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)21011-21023
Number of pages13
JournalJournal of Biological Chemistry
Volume283
Issue number30
DOIs
StatePublished - Jul 25 2008
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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