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000126217 0247_ $$2doi$$a10.1038/onc.2014.37
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000126217 0247_ $$2ISSN$$a1476-5594
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000126217 037__ $$aDKFZ-2017-02332
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000126217 1001_ $$aBuss, M. C.$$b0
000126217 245__ $$aThe WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants.
000126217 260__ $$aBasingstoke$$bNature Publ. Group$$c2015
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000126217 520__ $$aRecent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified upregulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1α activated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knockdown inhibited medulloblastoma growth and invasion. WIP1 knockdown also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knockdown inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knockdown inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4 and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate crosstalk among WIP1, CXCR4 and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.
000126217 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
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000126217 650_7 $$2NLM Chemicals$$aCXCL2 protein, human
000126217 650_7 $$2NLM Chemicals$$aCXCR4 protein, human
000126217 650_7 $$2NLM Chemicals$$aChemokine CXCL2
000126217 650_7 $$2NLM Chemicals$$aReceptors, CXCR4
000126217 650_7 $$0EC 2.7.11.16$$2NLM Chemicals$$aG-Protein-Coupled Receptor Kinase 5
000126217 650_7 $$0EC 2.7.11.16$$2NLM Chemicals$$aGRK5 protein, human
000126217 650_7 $$0EC 3.1.3.16$$2NLM Chemicals$$aPPM1D protein, human
000126217 650_7 $$0EC 3.1.3.16$$2NLM Chemicals$$aPhosphoprotein Phosphatases
000126217 650_7 $$0EC 3.1.3.16$$2NLM Chemicals$$aPpm1d protein, mouse
000126217 650_7 $$0EC 3.1.3.16$$2NLM Chemicals$$aProtein Phosphatase 2C
000126217 7001_ $$aRemke, M.$$b1
000126217 7001_ $$0P:(DE-HGF)0$$aLee, J.$$b2
000126217 7001_ $$aGandhi, K.$$b3
000126217 7001_ $$aSchniederjan, M. J.$$b4
000126217 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b5$$udkfz
000126217 7001_ $$0P:(DE-HGF)0$$aNorthcott, P. A.$$b6
000126217 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b7$$udkfz
000126217 7001_ $$aTaylor, M. D.$$b8
000126217 7001_ $$aCastellino, R. C.$$b9
000126217 773__ $$0PERI:(DE-600)2008404-3$$a10.1038/onc.2014.37$$gVol. 34, no. 9, p. 1126 - 1140$$n9$$p1126 - 1140$$tOncogene$$v34$$x1476-5594$$y2015
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000126217 9141_ $$y2015
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