Kenney Anna Marie, Widlund Hans R, Rowitch David H
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Development. 2004 Jan;131(1):217-28. doi: 10.1242/dev.00891. Epub 2003 Dec 3.
Neuronal precursor cells in the developing cerebellum require activity of the sonic hedgehog (Shh) and phosphoinositide-3-kinase (PI3K) pathways for growth and survival. Synergy between the Shh and PI3K signaling pathways are implicated in the cerebellar tumor medulloblastoma. Here, we describe a mechanism through which these disparate signaling pathways cooperate to promote proliferation of cerebellar granule neuron precursors. Shh signaling drives expression of mRNA encoding the Nmyc1 oncoprotein (previously N-myc), which is essential for expansion of cerebellar granule neuron precursors. The PI3K pathway stabilizes Nmyc1 protein via inhibition of GSK3-dependent Nmyc1 phosphorylation and degradation. The effects of PI3K activity on Nmyc1 stabilization are mimicked by insulin-like growth factor, a PI3K agonist with roles in central nervous system precursor growth and tumorigenesis. These findings indicate that Shh and PI3K signaling pathways converge on N-Myc to regulate neuronal precursor cell cycle progression. Furthermore, they provide a rationale for therapeutic targeting of PI3K signaling in medulloblastoma.
发育中小脑的神经元前体细胞的生长和存活需要音猬因子（Shh）和磷酸肌醇-3-激酶（PI3K）信号通路的活性。Shh和PI3K信号通路之间的协同作用与小脑肿瘤髓母细胞瘤有关。在此，我们描述了一种机制，通过该机制这些不同的信号通路协同促进小脑颗粒神经元前体细胞的增殖。Shh信号驱动编码Nmyc1癌蛋白（以前称为N-myc）的mRNA的表达，这对于小脑颗粒神经元前体细胞的扩增至关重要。PI3K信号通路通过抑制GSK3依赖的Nmyc1磷酸化和降解来稳定Nmyc1蛋白。胰岛素样生长因子（一种在中枢神经系统前体细胞生长和肿瘤发生中起作用的PI3K激动剂）模拟了PI3K活性对Nmyc1稳定的影响。这些发现表明，Shh和PI3K信号通路在N-Myc上汇聚以调节神经元前体细胞周期进程。此外，它们为髓母细胞瘤中PI3K信号通路的治疗靶向提供了理论依据。
