@article{f5b2aef58fd3449790f54ff02390f5cb,
title = "BAI1 Suppresses Medulloblastoma Formation by Protecting p53 from Mdm2-Mediated Degradation",
abstract = "Adhesion G protein-coupled receptors (ADGRs) encompass 33 human transmembrane proteins with long N termini involved in cell-cell and cell-matrix interactions. We show the ADGRB1 gene, which encodes Brain-specific angiogenesis inhibitor 1 (BAI1), is epigenetically silenced in medulloblastomas (MBs) through a methyl-CpG binding protein MBD2-dependent mechanism. Knockout of Adgrb1 in mice augments proliferation of cerebellar granule neuron precursors, and leads to accelerated tumor growth in the Ptch1+/− transgenic MB mouse model. BAI1 prevents Mdm2-mediated p53 polyubiquitination, and its loss substantially reduces p53 levels. Reactivation of BAI1/p53 signaling axis by a brain-permeable MBD2 pathway inhibitor suppresses MB growth in vivo. Altogether, our data define BAI1's physiological role in tumorigenesis and directly couple an ADGR to cancer formation. Zhu et al. identify epigenetic silencing of ADGRB1 in medulloblastoma (MB) and show that Adgrb1 loss in a transgenic mouse MB model accelerates tumor growth. ADGRB1 encodes BAI1, which prevents MDM2-mediated p53 polyubiquitination. Rescue of BAI1 expression increases p53 levels and suppresses MB growth.",
keywords = "ADGRB1, BAI1, GPCR, MBD2, Mdm2, brain tumor, epigenetic silencing, medulloblastoma, p53",
author = "Dan Zhu and Satoru Osuka and Zhaobin Zhang and Reichert, {Zachery R.} and Liquan Yang and Yonehiro Kanemura and Ying Jiang and Shuo You and Hanwen Zhang and Devi, {Narra S.} and Debanjan Bhattacharya and Shingo Takano and Gillespie, {G. Yancey} and Tobey Macdonald and Chalet Tan and Ryo Nishikawa and Nelson, {William G.} and Olson, {Jeffrey J.} and {Van Meir}, {Erwin G.}",
note = "Funding Information: We thank Dr. Tracy-Ann Read for providing Math1-GFP and Ptch1+/? transgenic mice, and Drs. Roger Abounader, Craig C. Castellino, and Bert Vogelstein for providing human tumor cell lines and RNA samples. We thank Dr. Oskar Laur from the Emory Custom Cloning Core Facility for generation of BAI1 mutant constructs. We thank Dr. Tomoko Shofuda and Ms. Ema Yoshioka for technical help with molecular subgrouping of MBs. We thank Drs. Peter Lichter, Ivo Buchhalter, Volker Hovestadt, and Marc Zapatka for providing access to prior published MB datasets. Research reported here was supported in part by Emory University Integrated Genomics Core (EIGC) and Cancer Tissue and Pathology Shared Resources of the Winship Cancer Institute. This work was supported by grants from the NIH, CA086335, CA163722, and NS096236 (to E.G.V.M.), CA138292 (to Winship Cancer Institute), NS055077 (to Center for Neurodegenerative Disease), CA151129 (to G.Y.G.) and the CURE Childhood Cancer Foundation, Southeastern Brain Tumor Foundation, St. Baldrick's Foundation, and the Emory Pediatric Research Center (to E.G.V.M.). MB samples were obtained from the Pediatric Brain Tumor Repository at Children's Healthcare of Atlanta, the University of Florida Brain Tumor Tissue Bank, the University of Alabama at Birmingham Patient Biospecimen Core and the NIH NeuroBioBank at the University of Maryland Brain and Tissue Bank. Funding Information: We thank Dr. Tracy-Ann Read for providing Math1- GFP and Ptch1 +/− transgenic mice, and Drs. Roger Abounader, Craig C. Castellino, and Bert Vogelstein for providing human tumor cell lines and RNA samples. We thank Dr. Oskar Laur from the Emory Custom Cloning Core Facility for generation of BAI1 mutant constructs. We thank Dr. Tomoko Shofuda and Ms. Ema Yoshioka for technical help with molecular subgrouping of MBs. We thank Drs. Peter Lichter, Ivo Buchhalter, Volker Hovestadt, and Marc Zapatka for providing access to prior published MB datasets. Research reported here was supported in part by Emory University Integrated Genomics Core (EIGC) and Cancer Tissue and Pathology Shared Resources of the Winship Cancer Institute. This work was supported by grants from the NIH , CA086335 , CA163722 , and NS096236 (to E.G.V.M.), CA138292 (to Winship Cancer Institute), NS055077 (to Center for Neurodegenerative Disease), CA151129 (to G.Y.G.) and the CURE Childhood Cancer Foundation , Southeastern Brain Tumor Foundation , St. Baldrick's Foundation , and the Emory Pediatric Research Center (to E.G.V.M.). MB samples were obtained from the Pediatric Brain Tumor Repository at Children's Healthcare of Atlanta, the University of Florida Brain Tumor Tissue Bank, the University of Alabama at Birmingham Patient Biospecimen Core and the NIH NeuroBioBank at the University of Maryland Brain and Tissue Bank. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jun,
day = "11",
doi = "10.1016/j.ccell.2018.05.006",
language = "English (US)",
volume = "33",
pages = "1004--1016.e5",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}