Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner
Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner
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DOI：
10.1101/gad.200907.112
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发表时间：
2012-12-01
影响因子：
10.5
通讯作者：
Gutmann, David H.
中科院分区：
文献类型：
--
作者：
Kaul, Aparna;Chen, Yi-Hsien;Gutmann, David H.
涉及BRAF激酶基因的串联重复最近被确定为散发性小儿胶质瘤中最常见的遗传改变，产生了一种具有增加BRAF活性的新型融合蛋白（f-BRAF）。为了确定f-BRAF在胶质瘤形成中的作用，我们证明了f-BRAF调节神经干细胞（NSC）而不是星形胶质细胞的增殖，并且足以在小鼠中诱导胶质瘤样病变。此外，f- braf驱动的NSC增殖源于tuberin/ rheb介导的哺乳动物雷帕霉素靶蛋白（mTOR）过度激活，导致s6激酶依赖性的p27降解。总的来说，这些结果表明mTOR通路激活是儿童散发性和家族性低级别胶质瘤共同的关键生长调节机制。
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.