TY  - JOUR
AU  - Mille, Frédéric
AU  - Tamayo-Orrego, Lukas
AU  - Lévesque, Martin
AU  - Remke, Marc
AU  - Korshunov, Andrey
AU  - Cardin, Julie
AU  - Bouchard, Nicolas
AU  - Izzi, Luisa
AU  - Kool, Marcel
AU  - Northcott, Paul A
AU  - Taylor, Michael D
AU  - Pfister, Stefan
AU  - Charron, Frédéric
TI  - The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors.
JO  - Developmental cell
VL  - 31
IS  - 1
SN  - 1534-5807
CY  - Cambridge, Mass.
PB  - Cell Press
M1  - DKFZ-2017-00536
SP  - 34 - 47
PY  - 2014
AB  - During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.
KW  - Boc protein, mouse (NLM Chemicals)
KW  - Hedgehog Proteins (NLM Chemicals)
KW  - Immunoglobulin G (NLM Chemicals)
KW  - PTCH protein, human (NLM Chemicals)
KW  - Patched Receptors (NLM Chemicals)
KW  - Patched-1 Receptor (NLM Chemicals)
KW  - Ptch1 protein, mouse (NLM Chemicals)
KW  - Receptors, Cell Surface (NLM Chemicals)
KW  - Shh protein, mouse (NLM Chemicals)
KW  - Cyclin D1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25263791
DO  - DOI:10.1016/j.devcel.2014.08.010
UR  - https://inrepo02.dkfz.de/record/119945
ER  -