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000120198 1001_ $$aHe, Xuelian$$b0
000120198 245__ $$aThe G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.
000120198 260__ $$aNew York, NY$$bNature America Inc.$$c2014
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000120198 520__ $$aMedulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.
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000120198 650_7 $$2NLM Chemicals$$aHedgehog Proteins
000120198 650_7 $$0E0399OZS9N$$2NLM Chemicals$$aCyclic AMP
000120198 650_7 $$0EC 3.6.5.1$$2NLM Chemicals$$aGTP-Binding Protein alpha Subunits, Gs
000120198 7001_ $$aZhang, Liguo$$b1
000120198 7001_ $$aChen, Ying$$b2
000120198 7001_ $$0P:(DE-HGF)0$$aRemke, Marc$$b3
000120198 7001_ $$aShih, David$$b4
000120198 7001_ $$aLu, Fanghui$$b5
000120198 7001_ $$aWang, Haibo$$b6
000120198 7001_ $$aDeng, Yaqi$$b7
000120198 7001_ $$aYu, Yang$$b8
000120198 7001_ $$aXia, Yong$$b9
000120198 7001_ $$aWu, Xiaochong$$b10
000120198 7001_ $$aRamaswamy, Vijay$$b11
000120198 7001_ $$aHu, Tom$$b12
000120198 7001_ $$aWang, Fan$$b13
000120198 7001_ $$aZhou, Wenhao$$b14
000120198 7001_ $$aBurns, Dennis K$$b15
000120198 7001_ $$00000-0001-7516-7372$$aKim, Se Hoon$$b16
000120198 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b17$$udkfz
000120198 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b18$$udkfz
000120198 7001_ $$aWeinstein, Lee S$$b19
000120198 7001_ $$aPomeroy, Scott L$$b20
000120198 7001_ $$aGilbertson, Richard J$$b21
000120198 7001_ $$aRubin, Joshua B$$b22
000120198 7001_ $$aHou, Yiping$$b23
000120198 7001_ $$aWechsler-Reya, Robert$$b24
000120198 7001_ $$aTaylor, Michael D$$b25
000120198 7001_ $$aLu, Q Richard$$b26
000120198 773__ $$0PERI:(DE-600)1484517-9$$a10.1038/nm.3666$$gVol. 20, no. 9, p. 1035 - 1042$$n9$$p1035 - 1042$$tNature medicine$$v20$$x1546-170X$$y2014
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