Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth.
Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth.
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DOI：
10.1016/j.devcel.2015.09.008
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发表时间：
2015-10-12
影响因子：
11.8
通讯作者：
Canettieri G
中科院分区：
文献类型：
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作者：
D'Amico D;Antonucci L;Di Magno L;Coni S;Sdruscia G;Macone A;Miele E;Infante P;Di Marcotullio L;De Smaele E;Ferretti E;Ciapponi L;Giangaspero F;Yates JR 3rd;Agostinelli E;Cardinali B;Screpanti I;Gulino A;Canettieri G
发育性刺猬信号控制小脑颗粒细胞前体（GCPs）的增殖，其异常激活是成神经管细胞瘤的主要原因。我们在这里表明，Hedgehog基因通过参与导致鸟氨酸脱羧酶（ODC）翻译的非规范轴，促进了GCPs中多胺的生物合成。这一过程由AMPK控制，AMPK在响应刺猬激活时磷酸化锌指蛋白CNBP的苏氨酸173。磷酸化的CNBP增加了与Sufu的关联，随后是CNBP稳定，ODC翻译和多胺生物合成。值得注意的是，CNBP、ODC和多胺在刺猬依赖型髓母细胞瘤中升高，遗传或药物抑制该轴有效地阻断了刺猬依赖型髓母细胞瘤细胞的体外和体内增殖。总之，这些数据说明了代谢控制的辅助机制，通过形态发生途径与发育和癌症相关。
Developmental Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs) and its aberrant activation is a leading cause of medulloblastoma. We show here that Hedgehog promotes polyamine biosynthesis in GCPs by engaging a non-canonical axis leading to the translation of ornithine decarboxylase (ODC). This process is governed by AMPK, which phosphorylates threonine 173 of the zinc finger protein CNBP in response to Hedgehog activation. Phosphorylated CNBP increases its association with Sufu, followed by CNBP stabilization, ODC translation and polyamine biosynthesis. Notably, CNBP, ODC and polyamines are elevated in Hedgehog-dependent medulloblastoma and genetic or pharmacological inhibition of this axis efficiently blocks Hedgehog-dependent proliferation of medulloblastoma cells in vitro and in vivo. Together, these data illustrate an auxiliary mechanism of metabolic control by a morphogenic pathway with relevant implications in development and cancer.