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

被引：50

作者：

Lawan, Ahmed ^{[1
]}

Al-Harthi, Sameer ^{[1
]}

Cadalbert, Laurence ^{[1
]}

McCluskey, Anthony G. ^{[1
]}

Shweash, Muhannad ^{[1
]}

Grassia, Gianluca ^{[1
]}

Grant, Anne ^{[1
]}

Boyd, Marie ^{[1
]}

Currie, Susan ^{[1
]}

Plevin, Robin ^{[1
]}

机构：

[1] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow G4 0NR, Lanark, Scotland

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2011年 / 286卷 / 15期

关键词：

N-TERMINAL-KINASE; PROTECTS ENDOTHELIAL-CELLS; DOUBLE-STRAND BREAKS; SIGNALING PATHWAYS; OXIDATIVE STRESS; EXPRESSION; APOPTOSIS; ACTIVATION; JNK; CANCER;

D O I：

10.1074/jbc.M110.181370

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：12933 / 12943

页数：11

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