Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.
School of Women's and Children's Health, UNSW Sydney, Randwick, NSW, Australia.
Nat Commun. 2021 Mar 25;12(1):1881. doi: 10.1038/s41467-021-22143-x.
To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies.
为了达到驱动恶性状态所需的非常高的癌蛋白水平，癌细胞利用泛素蛋白酶体系统上调转录因子水平。在这里，我们的分析确定了 A L Y R E F ，它来自神经母细胞瘤中最常见的染色体 17q21 端增益的遗传拷贝数变异，作为 M Y C N 蛋白周转的关键调节剂。我们在神经母细胞瘤的转基因模型中体外和体内显示 A L Y R E F 和 M Y C N 之间具有很强的协同作用。这两种蛋白质形成核共激活因子复合物，刺激泛素特异性肽酶 3 ， U S P 3 的转录。我们表明，U S P 3 水平的增加减少了 M Y C N 的 K-48 和 K-63 连接的泛素化，从而导致 M Y C N 蛋白稳定性增加。在 M Y C N - A L Y R E F - U S P 3 信号中，A L Y R E F 是 M Y C N 对恶性表型的影响和 U S P 3 对 M Y C N 稳定性的影响所必需的。这些数据定义了一个 M Y C N 癌蛋白依赖性状态，为未来的药理学研究提供了依据。
