%0 Journal Article
%A He, Xuelian
%A Zhang, Liguo
%A Chen, Ying
%A Remke, Marc
%A Shih, David
%A Lu, Fanghui
%A Wang, Haibo
%A Deng, Yaqi
%A Yu, Yang
%A Xia, Yong
%A Wu, Xiaochong
%A Ramaswamy, Vijay
%A Hu, Tom
%A Wang, Fan
%A Zhou, Wenhao
%A Burns, Dennis K
%A Kim, Se Hoon
%A Kool, Marcel
%A Pfister, Stefan
%A Weinstein, Lee S
%A Pomeroy, Scott L
%A Gilbertson, Richard J
%A Rubin, Joshua B
%A Hou, Yiping
%A Wechsler-Reya, Robert
%A Taylor, Michael D
%A Lu, Q Richard
%T The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.
%J Nature medicine
%V 20
%N 9
%@ 1546-170X
%C New York, NY
%I Nature America Inc.
%M DKFZ-2017-00780
%P 1035 - 1042
%D 2014
%X 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.
%K Hedgehog Proteins (NLM Chemicals)
%K Cyclic AMP (NLM Chemicals)
%K GTP-Binding Protein alpha Subunits, Gs (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:25150496
%2 pmc:PMC4334261
%R 10.1038/nm.3666
%U https://inrepo02.dkfz.de/record/120198