Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation.
Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation.
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DOI：
10.1038/onc.2009.333
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发表时间：
2010-01-21
期刊：
影响因子：
8
通讯作者：
Holmen, S. L.
中科院分区：
文献类型：
--
作者：
Robinson, J. P.;VanBrocklin, M. W.;Guilbeault, A. R.;Signorelli, D. L.;Brandner, S.;Holmen, S. L.
受体酪氨酸激酶（RTK）生长因子受体（EGFR、PDGFR、MET和ERBB 2）的突变导致RAS/RAF/MEK/ERK促分裂原活化蛋白激酶（MAPK）通路和PI（3）K/AKT通路的下游激活，几乎在所有高级别胶质瘤中发现，并且MAPK信号传导对于胶质瘤的持续维持是必需的。此外，BRAF在大多数低级别胶质瘤中突变，并且其表达和活性在大多数高级别胶质瘤中显著增加。虽然RTKS和RAS信号在胶质瘤发展中的重要性已得到证实，但BRAF的作用尚未得到表征。我们使用逆转录病毒RCAS/TVA系统将编码激活形式的BRAF、KRas、Akt和Cre的基因转移到Ink 4a/Arf lox/lox小鼠体内表达Nestin的神经祖细胞中，评估了激活的BRAF在胶质瘤形成中的作用。虽然单独表达活化的BRAF不足以用于肿瘤发生，但活化的BRAF和Akt或BRAF与Ink 4a/Arf缺失的组合是转化的。有趣的是，激活的BRAF产生的胶质瘤在Akt而不是Ink 4a/Arf丢失的情况下具有与激活的KRas相似的特征。我们的研究表明BRAF激活和信号传导在胶质瘤发展中的作用，并作为胶质瘤治疗的潜在靶点。
Mutations in receptor tyrosine kinase (RTK) growth factor receptors (EGFR, PDGFR, MET and ERBB2), which result in downstream activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/AKT pathway, are found in almost all high grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low grade gliomas and its expression and activity is significantly increased in the majority of high grade gliomas. While the importance of RTKs and RAS signaling in glioma development has been demonstrated, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral RCAS/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to Nestin expressing neural progenitor cells in Ink4a/Arf lox/lox mice in vivo. While expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with Ink4a/Arf loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not Ink4a/Arf loss. Our studies demonstrate a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.
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