TY  - JOUR
AU  - He, Xuelian
AU  - Zhang, Liguo
AU  - Chen, Ying
AU  - Remke, Marc
AU  - Shih, David
AU  - Lu, Fanghui
AU  - Wang, Haibo
AU  - Deng, Yaqi
AU  - Yu, Yang
AU  - Xia, Yong
AU  - Wu, Xiaochong
AU  - Ramaswamy, Vijay
AU  - Hu, Tom
AU  - Wang, Fan
AU  - Zhou, Wenhao
AU  - Burns, Dennis K
AU  - Kim, Se Hoon
AU  - Kool, Marcel
AU  - Pfister, Stefan
AU  - Weinstein, Lee S
AU  - Pomeroy, Scott L
AU  - Gilbertson, Richard J
AU  - Rubin, Joshua B
AU  - Hou, Yiping
AU  - Wechsler-Reya, Robert
AU  - Taylor, Michael D
AU  - Lu, Q Richard
TI  - The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.
JO  - Nature medicine
VL  - 20
IS  - 9
SN  - 1546-170X
CY  - New York, NY
PB  - Nature America Inc.
M1  - DKFZ-2017-00780
SP  - 1035 - 1042
PY  - 2014
AB  - Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.
KW  - Hedgehog Proteins (NLM Chemicals)
KW  - Cyclic AMP (NLM Chemicals)
KW  - GTP-Binding Protein alpha Subunits, Gs (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25150496
C2  - pmc:PMC4334261
DO  - DOI:10.1038/nm.3666
UR  - https://inrepo02.dkfz.de/record/120198
ER  -