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Protein neddylation and its alterations in human cancers for targeted therapy
Cellular Signalling ( IF 4.4 ) Pub Date : 2018-01-10 , DOI: 10.1016/j.cellsig.2018.01.009
Lisha Zhou , Wenjuan Zhang , Yi Sun , Lijun Jia

Neddylation, a post-translational modification that conjugates an ubiquitin-like protein NEDD8 to substrate proteins, is an important biochemical process that regulates protein function. The best-characterized substrates of neddylation are the cullin subunits of Cullin-RING ligases (CRLs), which, as the largest family of E3 ubiquitin ligases, control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. Recently, increasing pieces of experimental evidence strongly indicate that the process of protein neddylation modification is elevated in multiple human cancers, providing sound rationale for its targeting as an attractive anticancer therapeutic strategy. Indeed, neddylation inactivation by MLN4924 (also known as pevonedistat), a small molecule inhibitor of E1 NEDD8-activating enzyme currently in phase I/II clinical trials, exerts significant anticancer effects by inducing cell cycle arrest, apoptosis, senescence and autophagy in a cell-type and context dependent manner. Here, we summarize the latest progresses in the field with a major focus on preclinical studies in validation of neddylation modification as a promising anticancer target.



中文翻译:

靶向治疗中人类癌症中的蛋白质融合及其变化

Neddylation是将泛素样蛋白NEDD8与底物蛋白缀合的翻译后修饰,是调节蛋白功能的重要生化过程。最有代表性的底物化作用是Cullin-RING连接酶(CRL)的cullin亚基,它作为E3泛素连接酶的最大家族,可通过促进泛素化和随后各种酶的降解来控制许多重要的生物学过程,包括肿瘤发生。关键调节蛋白。最近,越来越多的实验证据强烈表明,在多种人类癌症中,蛋白质糖基化修饰的过程有所提高,为其靶向作为有吸引力的抗癌治疗策略提供了合理的依据。的确,MLN4924(也称为pevonedistat)会导致糊化作用失活,一种目前在I / II期临床试验中的E1 NEDD8活化酶的小分子抑制剂,通过诱导细胞周期停滞,凋亡,衰老和自噬,以细胞类型和背景相关的方式发挥重要的抗癌作用。在这里,我们总结了该领域的最新进展,主要侧重于临床前研究,以验证是否有可能将ND修饰作为有希望的抗癌靶标。

更新日期:2018-01-10
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