Deletion of the dual specific phosphatase-4 (DUSP-4) gene reveals an essential non-redundant role for MAP kinase phosphatase-2 (MKP-2) in proliferation and cell survival

Ahmed Lawan, Sameer Al-Harthi, Laurence Cadalbert, Anthony G. McCluskey, Muhannad Shweash, Gianluca Grassia, Anne Grant, Marie Boyd, Susan Currie, Robin Plevin

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36 Citations (Scopus)

Abstract

Mitogen-activated protein kinase phosphatase-2 (MKP-2) is a type 1 nuclear dual specific phosphatase (DUSP) implicated in a number of cancers. We examined the role of MKP-2 in the regulation of MAP kinase phosphorylation, cell proliferation, and survival responses in mouse embryonic fibroblasts (MEFs) derived from a novel MKP-2 (DUSP-4) deletion mouse. We show that serum and PDGF induced ERK-dependent MKP-2 expression in wild type METs but not in MKP-2(-/-) MEFs. PDGF stimulation of sustained ERK phosphorylation was enhanced in MKP-2(-/-) MEFs, whereas anisomycin-induced JNK was only marginally increased. However, marked effects upon cell growth parameters were observed. Cellular proliferation rates were significantly reduced in MKP-2(-/-) MEFs and associated with a significant increase in cell doubling time. Infection with adenoviral MKP-2 reversed the decrease in proliferation. Cell cycle analysis revealed a block in G(2)/M phase transition associated with cyclin B accumulation and enhanced cdc2 phosphorylation. MEFs from MKP-2(-/-) mice also showed enhanced apoptosis when stimulated with anisomycin correlated with increased caspase-3 cleavage and gamma H2AX phosphorylation. Increased apoptosis was reversed by adenoviral MKP-2 infection and correlated with selective inhibition of JNK signaling. Collectively, these data demonstrate for the first time a critical non-redundant role fir MKP-2 in regulating cell cycle progression and apoptosis.

Original languageEnglish
Pages (from-to)12933-12943
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number15
DOIs
Publication statusPublished - 15 Apr 2011

Keywords

  • N-terminal-kinase
  • protects endothelial-cells
  • double-strand breaks
  • signaling pathways
  • oxidative stress
  • express
  • apoptosis
  • activation
  • JNK
  • cancer

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