Insulin receptor substrate 1 is an effector of sonic hedgehog mitogenic signaling in cerebellar neural precursors.
Insulin receptor substrate 1 is an effector of sonic hedgehog mitogenic signaling in cerebellar neural precursors.
复制标题
DOI：
10.1242/dev.022871
复制
发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Kenney AM
中科院分区：
文献类型：
--
作者：
Parathath SR;Mainwaring LA;Fernandez-L A;Campbell DO;Kenney AM
Sonic hedgehog （Shh）和胰岛素样生长因子（IGF）信号对于许多组织的发育至关重要，并与成神经管细胞瘤（最常见的儿童实体恶性肿瘤）有关。小脑颗粒神经元前体（CGNPs）是某些类型的成神经管细胞瘤的来源细胞，在小脑发育过程中需要Shh和IGF信号传导来增殖和存活。我们询问Shh是否在增殖的CGNPs中调节IGF通路成分。我们报道，sh处理的CGNPs显示胰岛素受体底物1 （IRS1）蛋白水平升高，该蛋白也存在于发育中的小鼠小脑的生发层和小鼠sh诱导的髓母细胞瘤中。IRS1是其他细胞类型中igf介导的增殖所必需的致癌蛋白，先前在sh介导的CGNP增殖中尚未被描述。我们发现，在没有Shh的情况下，IRS1过表达可以维持CGNP的增殖。此外，慢病毒介导的敲除实验表明，IRS1活性是CGNP在切片外植体和游离培养物中增殖所必需的。与传统的专注于基因转录的Shh信号传导模型相反，Shh刺激并不调节IRS1的转录，而是通过干扰mtor依赖性的IRS1转换来稳定IRS1蛋白，并可能影响IRS1 mRNA的翻译。因此，我们已经确定IRS1作为Shh有丝分裂信号的新效应物，可能作为髓母细胞瘤治疗的未来靶点。我们的研究结果还表明，Shh和mTOR通路之间存在先前未报道的相互作用，并为发育过程中Shh介导的蛋白调控提供了一个非经典手段的例子。
Sonic hedgehog (Shh) and insulin-like growth factor (IGF) signaling are essential for development of many tissues and are implicated in medulloblastoma, the most common solid pediatric malignancy. Cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for certain classes of medulloblastomas, require Shh and IGF signaling for proliferation and survival during development of the cerebellum. We asked whether Shh regulates IGF pathway components in proliferating CGNPs. We report that Shh-treated CGNPs showed increased levels of insulin receptor substrate 1 (IRS1) protein, which was also present in the germinal layer of the developing mouse cerebellum and in mouse Shh-induced medulloblastomas. Previous roles for IRS1, an oncogenic protein essential for IGF-mediated proliferation in other cell types, have not been described in Shh-mediated CGNP proliferation. We found that IRS1 over-expression can maintain CGNP proliferation in the absence of Shh. Furthermore, lentivirus-mediated knock down experiments showed that IRS1 activity is required for CGNP proliferation in slice explants and dissociated cultures. Contrary to traditional models for Shh signaling which focus on gene transcription, Shh stimulation does not regulate IRS1 transcription but rather stabilizes IRS1 protein by interfering with mTOR-dependent IRS1 turnover and possibly affects IRS1 mRNA translation. Thus, we have identified IRS1 as a novel effector of Shh mitogenic signaling that may serve as a future target for medulloblastoma therapies. Our findings also indicate a previously unreported interaction between the Shh and mTOR pathways and provide an example of a non-classical means for Shh-mediated protein regulation during development.
登录
查看更多内容
影响因子：
8
作者：
del Rincón, SV;Guo, Q;Miller, WH
通讯作者：
Miller, WH
影响因子：
5.3
作者：
Aruga, J;Inoue, T;Mikoshiba, K
通讯作者：
Mikoshiba, K
影响因子：
56.9
作者：
Berman, DM;Karhadkar, SS;Beachy, PA
通讯作者：
Beachy, PA
影响因子：
4.8
作者：
Chen, J;Wu, A;Baserga, R
通讯作者：
Baserga, R
影响因子：
6
作者：
Hartmann, W;Koch, A;Pietsch, T
通讯作者：
Pietsch, T