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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytoma / pathology
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Astrocytoma / physiopathology
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Cell Proliferation
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Cells, Cultured
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Child
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Gene Expression Regulation, Neoplastic*
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Glioma / pathology*
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Glioma / physiopathology
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Humans
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Mice
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Mice, Inbred C57BL
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Monomeric GTP-Binding Proteins / metabolism
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Neuroglia / cytology*
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Neuroglia / metabolism
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Neuropeptides / metabolism
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Phosphorylation
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Ras Homolog Enriched in Brain Protein
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / metabolism
Substances
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Neuropeptides
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Ras Homolog Enriched in Brain Protein
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Rheb protein, mouse
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TSC2 protein, human
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Proto-Oncogene Proteins B-raf
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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ribosomal protein S6 kinase, 70kD, polypeptide 1
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Monomeric GTP-Binding Proteins