Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner
Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner
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DOI：
10.1073/pnas.1019012108
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发表时间：
2011-09-20
影响因子：
11.1
通讯作者：
Gutmann, David H.
中科院分区：
文献类型：
--
作者：
Banerjee, Sutapa;Crouse, Nikkilina R.;Gutmann, David H.
从人脑肿瘤和基因工程小鼠的分析中收集的证据表明，哺乳动物雷帕霉素靶蛋白（mTOR）通路是神经胶质细胞和神经胶质瘤细胞生长的中心调节因子。在这方面，神经纤维瘤病-1（NF 1）、结节性硬化症复合体（TSC）和PTEN基因的突变失活与神经胶质瘤形成相关，因此mTOR信号传导的药理学抑制导致肿瘤生长减弱。这种对mTOR的共同依赖性表明，PTEN和NF 1（神经纤维蛋白）神经胶质细胞生长调节需要TSC/Rheb（Ras同系物富集在脑中）控制mTOR功能。在这份报告中，我们使用的基因沉默在体外和有条件的小鼠转基因方法在体内相结合，以证明神经纤维蛋白调节星形胶质细胞的生长和胶质瘤形成的TSC/Rheb独立的方式。首先，我们发现Nf 1或Pten失活，而不是Tsc 1丢失或Rheb过表达，增加体外星形胶质细胞的生长。第二，Nf 1缺陷增加mTOR信号传导和星形胶质细胞过度增殖不受Rheb shRNA沉默的影响。第三，Nf 1（+/-）小鼠胶质祖细胞中条件性Tsc 1失活或Rheb过表达不会导致胶质瘤形成。总的来说，这些发现建立了TSC/Rheb独立的mTOR依赖性神经胶质细胞生长控制和神经胶质瘤发生机制，与神经胶质瘤个体治疗设计相关。
Converging evidence from the analysis of human brain tumors and genetically engineered mice has revealed that the mammalian target of rapamycin (mTOR) pathway is a central regulator of glial and glioma cell growth. In this regard, mutational inactivation of neurofibromatosis-1 (NF1), tuberous sclerosis complex (TSC), and PTEN genes is associated with glioma formation, such that pharmacologic inhibition of mTOR signaling results in attenuated tumor growth. This shared dependence on mTOR suggests that PTEN and NF1 (neurofibromin) glial growth regulation requires TSC/Rheb (Ras homolog enriched in brain) control of mTOR function. In this report, we use a combination of genetic silencing in vitro and conditional mouse transgenesis approaches in vivo to demonstrate that neurofibromin regulates astrocyte cell growth and glioma formation in a TSC/Rheb-independent fashion. First, we show that Nf1 or Pten inactivation, but not Tsc1 loss or Rheb overexpression, increases astrocyte cell growth in vitro. Second, Nf1-deficient increased mTOR signaling and astrocyte hyperproliferation is unaffected by Rheb shRNA silencing. Third, conditional Tsc1 inactivation or Rheb overexpression in glial progenitors of Nf1(+/-) mice does not lead to glioma formation. Collectively, these findings establish TSC/Rheb-independent mechanisms for mTOR-dependent glial cell growth control and gliomagenesis relevant to the design of therapies for individuals with glioma.