title: 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.
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 MEFs 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 γH2AX 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 for MKP-2 in regulating cell cycle progression and apoptosis.
authors.affiliation: Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, Scotland, United Kingdom.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Lawan
authors.forename: Sameer
authors.initials: S
authors.lastname: Al-Harthi
authors.forename: Laurence
authors.initials: L
authors.lastname: Cadalbert
authors.forename: Anthony G
authors.initials: AG
authors.lastname: McCluskey
authors.forename: Muhannad
authors.initials: M
authors.lastname: Shweash
authors.forename: Gianluca
authors.initials: G
authors.lastname: Grassia
authors.forename: Anne
authors.initials: A
authors.lastname: Grant
authors.forename: Marie
authors.initials: M
authors.lastname: Boyd
authors.forename: Susan
authors.initials: S
authors.lastname: Currie
authors.forename: Robin
authors.initials: R
authors.lastname: Plevin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D053148:Caspase 3; D019926:Cyclin B; D006657:Histones; D048670:MAP Kinase Kinase 4; D010982:Platelet-Derived Growth Factor; D017027:Protein Tyrosine Phosphatases; C522186:Dusp4 protein, mouse; C505409:Casp3 protein, mouse; C475961:gamma-H2AX protein, mouse