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@ARTICLE{Buss:126217,
author = {M. C. Buss and M. Remke and J. Lee and K. Gandhi and M. J.
Schniederjan and M. Kool$^*$ and P. A. Northcott$^*$ and S.
Pfister$^*$ and M. D. Taylor and R. C. Castellino},
title = {{T}he {WIP}1 oncogene promotes progression and invasion of
aggressive medulloblastoma variants.},
journal = {Oncogene},
volume = {34},
number = {9},
issn = {1476-5594},
address = {Basingstoke},
publisher = {Nature Publ. Group},
reportid = {DKFZ-2017-02332},
pages = {1126 - 1140},
year = {2015},
abstract = {Recent 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.},
keywords = {CXCL2 protein, human (NLM Chemicals) / CXCR4 protein, human
(NLM Chemicals) / Chemokine CXCL2 (NLM Chemicals) /
Receptors, CXCR4 (NLM Chemicals) / G-Protein-Coupled
Receptor Kinase 5 (NLM Chemicals) / GRK5 protein, human (NLM
Chemicals) / PPM1D protein, human (NLM Chemicals) /
Phosphoprotein Phosphatases (NLM Chemicals) / Ppm1d protein,
mouse (NLM Chemicals) / Protein Phosphatase 2C (NLM
Chemicals)},
cin = {B062},
ddc = {610},
cid = {I:(DE-He78)B062-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:24632620},
pmc = {pmc:PMC4722800},
doi = {10.1038/onc.2014.37},
url = {https://inrepo02.dkfz.de/record/126217},
}