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Nat Med. 2014 Sep;20(9):1035-42. doi: 10.1038/nm.3666. Epub 2014 Aug 24.

The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.

Author information

1
1] Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China. [2] Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
2
Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
3
School of Life Sciences, Xiamen University, Fujian, China.
4
The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
5
Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.
6
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
7
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, USA.
8
Department of Forensic Medicine, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, School of Preclinical and Forensic Medicine, West China Second Hospital, Sichuan University, Chengdu, China.
9
Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
10
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
11
Division of Pediatric Neurooncology, German Cancer Research Center, Heidelberg, Germany.
12
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
13
Department of Neurology, Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
14
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
15
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
16
Tumor Development Program, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
17
1] Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [2] Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China. [3] Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.

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 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.

PMID:
25150496
PMCID:
PMC4334261
DOI:
10.1038/nm.3666
[Indexed for MEDLINE]
Free PMC Article

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