The G protein α subunit Gα s is a tumor suppressor in Sonic hedgehog-driven medulloblastoma

Xuelian He, Liguo Zhang, Ying Chen, Marc Remke, David Shih, Fanghui Lu, Haibo Wang, Yaqi Deng, Yang Yu, Yong Xia, Xiaochong Wu, Vijay Ramaswamy, Tom Hu, Fan Wang, Wenhao Zhou, Dennis K. Burns, SeHoon Kim, Marcel Kool, Stefan M. Pfister, Lee S. Weinstein & 7 others Scott L. Pomeroy, Richard J. Gilbertson, Joshua B. Rubin, Yiping Hou, Robert Wechsler-Reya, Michael D. Taylor, Q. Richard Lu

Research output: Contribution to journalArticle

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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 Gα s, 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. Gα s 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 G7alpha; s 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 Gα s that can be found consistently across Shh-group medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.

Original languageEnglish
Pages (from-to)1035-1042
Number of pages8
JournalNature Medicine
Volume20
Issue number9
DOIs
Publication statusPublished - 2014 Sep 1

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Medulloblastoma
Hedgehogs
Protein Subunits
GTP-Binding Proteins
Tumors
Neoplasms
Genes
Cell proliferation
Ablation
Cilia
Neurons
Brain
Tumor Suppressor Genes
Brain Neoplasms
Modulation
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

He, X., Zhang, L., Chen, Y., Remke, M., Shih, D., Lu, F., ... Lu, Q. R. (2014). The G protein α subunit Gα s is a tumor suppressor in Sonic hedgehog-driven medulloblastoma Nature Medicine, 20(9), 1035-1042. https://doi.org/10.1038/nm.3666
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, SeHoon ; Kool, Marcel ; Pfister, Stefan M. ; Weinstein, Lee S. ; Pomeroy, Scott L. ; Gilbertson, Richard J. ; Rubin, Joshua B. ; Hou, Yiping ; Wechsler-Reya, Robert ; Taylor, Michael D. ; Lu, Q. Richard. / The G protein α subunit Gα s is a tumor suppressor in Sonic hedgehog-driven medulloblastoma In: Nature Medicine. 2014 ; Vol. 20, No. 9. pp. 1035-1042.
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He, X, Zhang, L, Chen, Y, Remke, M, Shih, D, Lu, F, Wang, H, Deng, Y, Yu, Y, Xia, Y, Wu, X, Ramaswamy, V, Hu, T, Wang, F, Zhou, W, Burns, DK, Kim, S, Kool, M, Pfister, SM, Weinstein, LS, Pomeroy, SL, Gilbertson, RJ, Rubin, JB, Hou, Y, Wechsler-Reya, R, Taylor, MD & Lu, QR 2014, ' The G protein α subunit Gα s is a tumor suppressor in Sonic hedgehog-driven medulloblastoma ', Nature Medicine, vol. 20, no. 9, pp. 1035-1042. https://doi.org/10.1038/nm.3666

The G protein α subunit Gα s is a tumor suppressor in Sonic hedgehog-driven medulloblastoma . / 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, SeHoon; Kool, Marcel; Pfister, Stefan M.; Weinstein, Lee S.; Pomeroy, Scott L.; Gilbertson, Richard J.; Rubin, Joshua B.; Hou, Yiping; Wechsler-Reya, Robert; Taylor, Michael D.; Lu, Q. Richard.

In: Nature Medicine, Vol. 20, No. 9, 01.09.2014, p. 1035-1042.

Research output: Contribution to journalArticle

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T1 - The G protein α subunit Gα s is a tumor suppressor in Sonic hedgehog-driven medulloblastoma

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, SeHoon

AU - Kool, Marcel

AU - Pfister, Stefan M.

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

PY - 2014/9/1

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N2 - 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 Gα s, 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. Gα s 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 G7alpha; s 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 Gα s 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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