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

Research output: Contribution to journalArticle

31 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.

LanguageEnglish
Pages12933-12943
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number15
DOIs
Publication statusPublished - 15 Apr 2011

Fingerprint

Mitogen-Activated Protein Kinase 1
Essential Genes
Phosphoric Monoester Hydrolases
Cell Survival
Phosphotransferases
Genes
Cells
Fibroblasts
Phosphorylation
Anisomycin
Apoptosis
Cell Cycle
Mitogen-Activated Protein Kinase Phosphatases
Cell Proliferation
Cyclin B
Protein Phosphatase 2
Phase Transition
Extracellular Signal-Regulated MAP Kinases
Cell proliferation
Cell growth

Keywords

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

Cite this

Lawan, Ahmed ; Al-Harthi, Sameer ; Cadalbert, Laurence ; McCluskey, Anthony G. ; Shweash, Muhannad ; Grassia, Gianluca ; Grant, Anne ; Boyd, Marie ; Currie, Susan ; Plevin, Robin. / 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. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 15. pp. 12933-12943.
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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.",
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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. / Lawan, Ahmed; Al-Harthi, Sameer; Cadalbert, Laurence; McCluskey, Anthony G.; Shweash, Muhannad; Grassia, Gianluca; Grant, Anne; Boyd, Marie; Currie, Susan; Plevin, Robin.

In: Journal of Biological Chemistry, Vol. 286, No. 15, 15.04.2011, p. 12933-12943.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Lawan, Ahmed

AU - Al-Harthi, Sameer

AU - Cadalbert, Laurence

AU - McCluskey, Anthony G.

AU - Shweash, Muhannad

AU - Grassia, Gianluca

AU - Grant, Anne

AU - Boyd, Marie

AU - Currie, Susan

AU - Plevin, Robin

PY - 2011/4/15

Y1 - 2011/4/15

N2 - 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.

AB - 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.

KW - N-terminal-kinase

KW - protects endothelial-cells

KW - double-strand breaks

KW - signaling pathways

KW - oxidative stress

KW - express

KW - apoptosis

KW - activation

KW - JNK

KW - cancer

U2 - 10.1074/jbc.M110.181370

DO - 10.1074/jbc.M110.181370

M3 - Article

VL - 286

SP - 12933

EP - 12943

JO - Journal of Biological Chemistry

T2 - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

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ER -