Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15996-6001. doi: 10.1073/pnas.1019012108. Epub 2011 Sep 6.
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.
来自人类脑瘤分析和基因工程小鼠的汇聚证据表明，哺乳动物雷帕霉素靶蛋白（mTOR）途径是神经胶质细胞和神经胶质瘤细胞生长的中央调节剂。在这方面，神经纤维瘤病 1（NF1）、结节性硬化症复合物（TSC）和 PTEN 基因的突变失活与神经胶质瘤的形成有关，因此，mTOR 信号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 NF1（神经纤维瘤蛋白）对神经胶质生长的调节需要 TSC/Rheb（富含大脑的 Ras 同源物）控制 mTOR 功能。在本报告中，我们使用体外基因沉默和体内条件性转基因方法相结合，证明神经纤维瘤蛋白以 TSC/Rheb 独立的方式调节星形胶质细胞的生长和神经胶质瘤的形成。首先，我们表明，Nf1 或 Pten 的失活，但不是 Tsc1 的缺失或 Rheb 的过表达，会增加体外星形胶质细胞的生长。其次，Nf1 缺陷增加 mTOR 信号和星形胶质细胞过度增殖不受 Rheb shRNA 沉默的影响。第三，条件性 Tsc1 失活或 Rheb 过表达在 Nf1(+/-)小鼠的神经胶质前体细胞中不会导致神经胶质瘤的形成。总之，这些发现确立了 TSC/Rheb 独立的 mTOR 依赖性神经胶质细胞生长控制机制和神经胶质瘤发生，这与为神经胶质瘤患者设计治疗方法有关。
