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.
| Language | English |
|---|---|
| Pages | 12933-12943 |
| Number of pages | 11 |
| Journal | Journal of Biological Chemistry |
| Volume | 286 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - 15 Apr 2011 |
Fingerprint
Keywords
- N-terminal-kinase
- protects endothelial-cells
- double-strand breaks
- signaling pathways
- oxidative stress
- express
- apoptosis
- activation
- JNK
- cancer
Cite this
}
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 journal › Article
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
IS - 15
ER -