title: Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner.
abstract: Tandem duplications involving the BRAF kinase gene have recently been identified as the most frequent genetic alteration in sporadic pediatric glioma, creating a novel fusion protein (f-BRAF) with increased BRAF activity. To define the role of f-BRAF in gliomagenesis, we demonstrate that f-BRAF regulates neural stem cell (NSC), but not astrocyte, proliferation and is sufficient to induce glioma-like lesions in mice. Moreover, f-BRAF-driven NSC proliferation results from tuberin/Rheb-mediated mammalian target of rapamycin (mTOR) hyperactivation, leading to S6-kinase-dependent degradation of p27. Collectively, these results establish mTOR pathway activation as a key growth regulatory mechanism common to both sporadic and familial low-grade gliomas in children.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Kaul
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Chen
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Emnett
authors.forename: Sonika
authors.initials: S
authors.lastname: Dahiya
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D048493:Proto-Oncogene Proteins B-raf; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020559:Monomeric GTP-Binding Proteins