非经典刺猬信号通路/AMPK介导的多胺代谢调控支持神经元和髓母细胞瘤细胞生长。
Non-canonical Hedgehog/AMPK-Mediated Control of Polyamine Metabolism Supports Neuronal and Medulloblastoma Cell Growth.
作者信息
D'Amico Davide, Antonucci Laura, Di Magno Laura, Coni Sonia, Sdruscia Giulia, Macone Alberto, Miele Evelina, Infante Paola, Di Marcotullio Lucia, De Smaele Enrico, Ferretti Elisabetta, Ciapponi Laura, Giangaspero Felice, Yates John R, Agostinelli Enzo, Cardinali Beatrice, Screpanti Isabella, Gulino Alberto, Canettieri Gianluca
机构信息
Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy.
Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy; Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome 00161, Italy.
出版信息
Dev Cell. 2015 Oct 12;35(1):21-35. doi: 10.1016/j.devcel.2015.09.008.
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.
发育中的刺猬信号通路控制小脑颗粒细胞前体（GCPs）的增殖，其异常激活是髓母细胞瘤的主要原因。我们在此表明，刺猬信号通路通过参与一条非经典轴来促进GCPs中的多胺生物合成，该轴导致鸟氨酸脱羧酶（ODC）的翻译。这一过程由AMPK调控，AMPK在刺猬信号通路激活时磷酸化锌指蛋白CNBP的苏氨酸173。磷酸化的CNBP增加其与Sufu的结合，随后CNBP稳定、ODC翻译和多胺生物合成。值得注意的是，CNBP、ODC和多胺在依赖刺猬信号通路的髓母细胞瘤中升高，对该轴的基因或药理学抑制可有效阻断体外和体内髓母细胞瘤细胞依赖刺猬信号通路的增殖。总之，这些数据说明了形态发生途径对代谢控制的一种辅助机制，这在发育和癌症中具有相关意义。
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