title: Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRasQ61L)-driven SerpinB2 expression.
abstract: Ectopic expression of dual-specificity phosphatase 5 (DUSP5), an inducible mitogen-activated protein (MAP) kinase phosphatase, specifically inactivates and anchors extracellular signal-regulated kinase (ERK)1/2 in the nucleus. However, the role of endogenous DUSP5 in regulating the outcome of Ras/ERK kinase signaling under normal and pathological conditions is unknown. Here we report that mice lacking DUSP5 show a greatly increased sensitivity to mutant Harvey-Ras (HRas(Q61L))-driven papilloma formation in the 7,12-Dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA) model of skin carcinogenesis. Furthermore, mouse embryo fibroblasts (MEFs) from DUSP5(-/-) mice show increased levels of nuclear phospho-ERK immediately after TPA stimulation and fail to accumulate total ERK in the nucleus compared with DUSP5(+/+) cells. Surprisingly, a microarray analysis reveals that only a small number of Ras/ERK-dependent TPA-responsive transcripts are up-regulated on deletion of DUSP5 in MEFs and mouse skin. The most up-regulated gene on DUSP5 loss encodes SerpinB2, an inhibitor of extracellular urokinase plasminogen activator and deletion of DUSP5 acts synergistically with mutant HRas(Q61L) and TPA to activate ERK-dependent SerpinB2 expression at the transcriptional level. SerpinB2 has previously been implicated as a mediator of DMBA/TPA-induced skin carcinogenesis. By analyzing DUSP5(-/-), SerpinB2(-/-) double knockout mice, we demonstrate that deletion of SerpinB2 abrogates the increased sensitivity to papilloma formation seen on DUSP5 deletion. We conclude that DUSP5 performs a key nonredundant role in regulating nuclear ERK activation, localization, and gene expression. Furthermore, our results suggest an in vivo role for DUSP5 as a tumor suppressor by modulating the oncogenic potential of activated Ras in the epidermis.
authors.affiliation: Cancer Research-UK Stress Response Laboratory, Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom;
authors.forename: Linda K
authors.initials: LK
authors.lastname: Rushworth
authors.affiliation: Cancer Research-UK Stress Response Laboratory, Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom;
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kidger
authors.affiliation: Cancer Research-UK Stress Response Laboratory, Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom;
authors.forename: Laurent
authors.initials: L
authors.lastname: Delavaine
authors.affiliation: Cancer Research-UK Stress Response Laboratory, Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom;
authors.forename: Graeme
authors.initials: G
authors.lastname: Stewart
authors.affiliation: Cancer Research-UK Stress Response Laboratory, Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom;
authors.forename: Susanne
authors.initials: S
authors.lastname: van Schelven
authors.affiliation: Cancer Research-UK Stress Response Laboratory, Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom;
authors.forename: Jane
authors.initials: J
authors.lastname: Davidson
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom; and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bryant
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom; and.
authors.forename: Edward
authors.initials: E
authors.lastname: Caddye
authors.affiliation: Bioinformatics and Biostatistics Group, Cancer Research-UK London Research Institute, London WC2A 3LY, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: East
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom; and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Caunt
authors.affiliation: Cancer Research-UK Stress Response Laboratory, Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom; s.m.keyse@dundee.ac.uk.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Keyse
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology*; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D011905:Genes, ras; D051379:Mice; D018345:Mice, Knockout; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
chemical_list: D017396:Plasminogen Activator Inhibitor 2; D015127:9,10-Dimethyl-1,2-benzanthracene; D048049:Extracellular Signal-Regulated MAP Kinases; D054637:Dual-Specificity Phosphatases; C546197:Dusp5 protein, mouse; D013755:Tetradecanoylphorbol Acetate
keywords: DUSP5; MAP kinase; SerpinB2; protein phosphatase; skin cancer