The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma
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 suppre...
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| Format: | Online |
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2014
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334261/ |
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pubmed-43342612015-03-01 The G-protein Alpha Subunit Gsα 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, Se Hoon 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 Article 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. 2014-08-24 2014-09 /pmc/articles/PMC4334261/ /pubmed/25150496 http://dx.doi.org/10.1038/nm.3666 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
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Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
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NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| 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. Pomeroy, Scott L. Gilbertson, Richard J. Rubin, Joshua B. Hou, Yiping Wechsler-Reya, Robert Taylor, Michael D. Lu, Q. Richard |
| spellingShingle |
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. Pomeroy, Scott L. Gilbertson, Richard J. Rubin, Joshua B. Hou, Yiping Wechsler-Reya, Robert Taylor, Michael D. Lu, Q. Richard The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma |
| author_facet |
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. Pomeroy, Scott L. Gilbertson, Richard J. Rubin, Joshua B. Hou, Yiping Wechsler-Reya, Robert Taylor, Michael D. Lu, Q. Richard |
| author_sort |
He, Xuelian |
| title |
The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma |
| title_short |
The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma |
| title_full |
The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma |
| title_fullStr |
The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma |
| title_full_unstemmed |
The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma |
| title_sort |
g-protein alpha subunit gsα is a tumor suppressor in sonic hedgehog-driven medulloblastoma |
| description |
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. |
| publishDate |
2014 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334261/ |
| _version_ |
1613190401440612352 |