The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma
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Author
He, Xuelian
Zhang, Liguo
Chen, Ying
Remke, Marc
Shih, David
Lu, Fanghui
Wang, Haibo
Deng, Yaqi
Yu, Yang
Xia, Yong
Wu, Xiaochong
Ramaswamy, Vijay
Hu, Tom
Wang, Fan
Zhou, Wenhao
Burns, Dennis K.
Kim, Se Hoon
Kool, Marcel
Pfister, Stefan M.
Weinstein, Lee S.
Gilbertson, Richard J.
Rubin, Joshua B.
Hou, Yiping
Wechsler-Reya, Robert
Taylor, Michael D.
Lu, Q. Richard
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nm.3666Metadata
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He, X., L. Zhang, Y. Chen, M. Remke, D. Shih, F. Lu, H. Wang, et al. 2014. “The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma.” Nature medicine 20 (9): 1035-1042. doi:10.1038/nm.3666. http://dx.doi.org/10.1038/nm.3666.Abstract
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 Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα 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 of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas mutants. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, illuminating G-protein modulation as a potential therapeutic avenue.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334261/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:14351378
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