Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner
- 1Department of Neurology,
- 2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63108, USA
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↵3 These authors contributed equally to this work.
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.
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Footnotes
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↵4 Corresponding author
E-mail gutmannd{at}neuro.wustl.edu
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.200907.112.
- Received July 10, 2012.
- Accepted October 10, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press