Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Biochem Soc Trans. 2021 Feb 26;49(1):519-529. doi: 10.1042/BST20201060.
The ubiquitin proteasome system (UPS) serves as the major posttranslational modification system for the maintenance of protein homeostasis. The ubiquitin ligases (E3s) are responsible for the recognition and recruitment of specific substrate proteins for polyubiquitination. Really interesting new gene (RING) finger E3s account for the majority of E3s. The human genome encodes more than 600 RING E3s, which are divided into three subclasses: single polypeptide E3s, cullin-RING ligases (CRLs) and other multisubunit E3s. The abnormal regulation of RING E3s has been reported to disrupt normal biological processes and induce the occurrence of many human malignancies. Glioma is the most common type of malignant primary brain tumor. In the last few decades, patient prognosis has improved as novel targeted therapeutic agents have developed. In this review, we will summarize the current knowledge about the dysregulation of RING E3s and the altered stability of their substrates in glioma. We will further introduce and discuss the current status and future perspectives of the application of small inhibitors and proteolysis-targeting chimeric molecules (PROTACs) interfering with RING E3s as potential anticancer agents for glioma.
泛素蛋白酶体系统 (UPS) 作为维持蛋白质内稳态的主要翻译后修饰系统。泛素连接酶 (E3s) 负责识别和募集特定的底物蛋白进行多泛素化。真正有趣的新基因 (RING) 指 E3s 占 E3s 的大多数。人类基因组编码了超过 600 种 RING E3s，它们分为三类：单多肽 E3s、cullin-RING 连接酶 (CRLs) 和其他多亚基 E3s。已经报道 RING E3s 的异常调节会破坏正常的生物学过程，并诱导许多人类恶性肿瘤的发生。神经胶质瘤是最常见的恶性原发性脑肿瘤。在过去的几十年中，随着新型靶向治疗药物的发展，患者的预后得到了改善。在这篇综述中，我们将总结 RING E3s 失调及其底物稳定性改变在神经胶质瘤中的最新知识。我们将进一步介绍和讨论小分子抑制剂和蛋白水解靶向嵌合分子 (PROTACs) 干扰 RING E3s 作为神经胶质瘤潜在抗癌药物的应用现状和未来展望。
