The mammalian Hedgehog pathway is modulated by ANP32 proteins.
The mammalian Hedgehog pathway is modulated by ANP32 proteins.
复制标题
DOI：
10.1016/j.bbrc.2021.03.027
复制
发表时间：
2021-03
影响因子：
3.1
通讯作者：
A. Hupfer;A. Brichkina;Till Adhikary;M. Lauth
中科院分区：
文献类型：
--
作者：
A. Hupfer;A. Brichkina;Till Adhikary;M. Lauth
髓母细胞瘤是儿童最常见的恶性脑肿瘤。迄今为止，转录谱描绘了四个主要的MB亚组，其中一个由不受控制的Hedgehog（Hh）信号传导（SHH-MB）驱动。该途径适合于药物靶向，但临床批准的化合物仅靶向跨膜组分Smoothened（SMO）。不幸的是，经常遇到对SMO抑制剂的耐药性，使得新的Hh通路组分的鉴定成为强制性的，这可能在未来成为新的药物靶点。在这里，我们已经使用MB作为一种工具来描绘新的调制器的Hh信号，并确定了酸性核磷蛋白32（ANP 32）家族的蛋白质作为新的监管机构。所有三个家族成员（ANP 32A、ANP 32 B、ANP 32 E）的表达在Hh诱导的MB中增加，并且它们的表达水平与SHH-MB患者的总体存活率负相关。从机制上讲，我们可以发现ANP 32蛋白作为GLI转录因子上游哺乳动物Hh信号传导的正调节剂发挥作用。这些发现为哺乳动物Hh信号级联增加了迄今未知的调节剂，并可能刺激未来的翻译努力，以对抗Hh驱动的恶性肿瘤。
Medulloblastoma (MB) is the most common malignant brain tumor in children. Transcriptional profiling has so far delineated four major MB subgroups of which one is driven by uncontrolled Hedgehog (Hh) signaling (SHH-MB). This pathway is amenable to drug targeting, yet clinically approved compounds exclusively target the transmembrane component Smoothened (SMO). Unfortunately, drug resistance against SMO inhibitors is encountered frequently, making the identification of novel Hh pathway components mandatory, which could serve as novel drug targets in the future. Here, we have used MB as a tool to delineate novel modulators of Hh signaling and have identified the Acidic Nuclear Phosphoprotein 32 (ANP32) family of proteins as novel regulators. The expression of all three family members (ANP32A, ANP32B, ANP32E) is increased in Hh-induced MB and their expression level is negatively associated with overall survival in SHH-MB patients. Mechanistically, we could find that ANP32 proteins function as positive modulators of mammalian Hh signaling upstream of GLI transcription factors. These findings add hitherto unknown regulators to the mammalian Hh signaling cascade and might spur future translational efforts to combat Hh-driven malignancies.