机构：[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[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四川大学华西医院[7]Department of Pathology, University of Texas Southwestern Medical Center, Dallas, USA[8]Key Laboratory of Birth Defects, Children’s Hospital of Fudan University, Shanghai, China[9]Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea[10]Division of Pediatric Neurooncology, German Cancer Research Center, Heidelberg, Germany[11]Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA[12]Department of Neurology, Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA[13]Department of Developmental Neurobiology, St.Jude Children’s Research Hospital, Memphis, Tennessee, USA[14]Department of Pediatrics, Washington University School of Medicine, St.Louis, Missouri, USA[15]Tumor Development Program, Sanford-Burnham Medical Research Institute, La Jolla, California, USA
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.
基金：
This study was funded in part by grants from the US National Institutes
of Health (R01 NS078092 and R01 NS075243) to Q.R.L., the Ministry of Education
of China (IRT0935) and from the Canadian Institutes of Health Research to M.D.T. and a postdoctoral fellowship by the Mildred-Scheel Foundation/German
Cancer Aid (M.R.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2014]版：
大类|1 区医学
小类|1 区生化与分子生物学1 区细胞生物学1 区医学：研究与实验
最新[2023]版：
大类|1 区医学
小类|1 区生化与分子生物学1 区细胞生物学1 区医学：研究与实验
第一作者：
第一作者机构：[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
通讯作者：
通讯机构：[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[5]Department of Pediatrics, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China[8]Key Laboratory of Birth Defects, Children’s Hospital of Fudan University, Shanghai, China
推荐引用方式(GB/T 7714)：
Xuelian He,Liguo Zhang,Ying Chen,et al.The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.[J].Nature medicine.2014,20(9):1035-42.doi:10.1038/nm.3666.
APA：
Xuelian He,Liguo Zhang,Ying Chen,Marc Remke,David Shih...&Q Richard Lu.(2014).The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma..Nature medicine,20,(9)
MLA：
Xuelian He,et al."The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma.".Nature medicine 20..9(2014):1035-42
医学