Tuberous Sclerosis Complex Suppression in Cerebellar Development and Medulloblastoma: Separate Regulation of Mammalian Target of Rapamycin Activity and p27Kip1 Localization
Tuberous Sclerosis Complex Suppression in Cerebellar Development and Medulloblastoma: Separate Regulation of Mammalian Target of Rapamycin Activity and p27Kip1 Localization
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DOI：
10.1158/0008-5472.can-09-1299
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发表时间：
2009-09-15
期刊：
影响因子：
11.2
通讯作者：
Kenney, Anna Marie
中科院分区：
文献类型：
--
作者：
Bhatia, Bobby;Northcott, Paul A.;Kenney, Anna Marie
在发育过程中，小脑颗粒神经元前体细胞（CGNP）（儿科脑肿瘤髓母细胞瘤的候选细胞）的增殖需要 Sonic Hedgehog（Shh）和胰岛素样生长因子（IGF）的信号传导，其信号通路也与髓母细胞瘤有关。 IGF 信号传导的后果之一是抑制哺乳动物雷帕霉素靶标 (mTOR) 的结节性硬化症复合体 (TSC)（由 TSC1 和 TSC2 组成）失活，导致 mRNA 翻译增加。我们发现，TSC 功能受损的小鼠表现出 mTOR 通路激活增加、CGNP 增殖增强、糖原合酶激酶 3 α/β (GSK-3 α/β) 失活以及细胞周期蛋白依赖性激酶抑制剂 p27 (Kip1) 的细胞质定位，这被认为是导致其失活或获得致癌功能的原因。我们在 CGNP 野生型原代培养物（其中 TSC1 和/或 TSC2 被敲低）以及异位 Shh 通路激活诱导的小鼠髓母细胞瘤中观察到相同的特征。此外，Shh 诱导的小鼠髓母细胞瘤表现出 Akt 介导的 TSC2 失活，突变的 TSC2 等位基因与异常的 Shh 信号协同作用，增加了小鼠髓母细胞瘤的发病率。在Shh诱导的髓母细胞瘤细胞中驱动外源TSC2表达可纠正p27（Kip1）定位并减少增殖。体内肿瘤和原代 CGNP 培养物中 GSK-3 α/β 失活是 mTOR 依赖性的，而 p27(Kip1) 细胞质定位受 TSC2 调节 mTOR 上游。这些结果表明，Shh 有丝分裂信号传导与 TSC 功能调节新蛋白质合成和细胞周期蛋白依赖性激酶抑制之间的平衡对于肿瘤的正常发展和预防至关重要。
During development, proliferation of cerebellar granule neuron precursors (CGNP), candidate cells-of-origin for the pediatric brain tumor medulloblastoma, requires signaling by Sonic hedgehog (Shh) and insulin-like growth factor (IGF), the pathways of which are also implicated in medulloblastoma. One of the consequences of IGF signaling is inactivation of the mammalian target of rapamycin (mTOR)-suppressing tuberous sclerosis complex (TSC), comprised of TSC1 and TSC2, leading to increased mRNA translation. We show that mice, in which TSC function is impaired, display increased mTOR pathway activation, enhanced CGNP proliferation, glycogen synthase kinase-3 alpha/beta (GSK-3 alpha/beta) inactivation, and cytoplasmic localization of the cyclin-dependent kinase inhibitor p27(Kip1), which has been proposed to cause its inactivation or gain of oncogenic functions. We observed the same characteristics in wild-type primary cultures of CGNPs in which TSC1 and/or TSC2 were knocked down, and in mouse medulloblastomas induced by ectopic Shh pathway activation. Moreover, Shh-induced mouse medulloblastomas manifested Akt-mediated TSC2 inactivation, and the mutant TSC2 allele svnergized with aberrant Shh signaling to increase medulloblastoma incidence in mice. Driving exogenous TSC2 expression in Shh-induced medulloblastoma cells corrected p27(Kip1) localization and reduced proliferation. GSK-3 alpha/beta inactivation in the tumors in vivo and in primary CGNP cultures was mTOR-dependent, whereas p27(Kip1) cytoplasmic localization was regulated upstream of mTOR by TSC2. These results indicate that a balance between Shh mitogenic signaling and TSC function regulating new protein synthesis and cyclin-dependent kinase inhibition is essential for the normal development and prevention of tumor