Oncogenic Signaling Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Adv Exp Med Biol. 2020;1233:3-28. doi: 10.1007/978-3-030-38266-7_1.
Ubiquitin ligases (E3) play a crucial role in the regulation of different cellular processes such as proliferation and differentiation via recognition, interaction, and ubiquitination of key cellular proteins in a spatial and temporal regulated manner. The type of ubiquitin chain formed determines the fate of the substrates. The ubiquitinated substrates can be degraded by the proteasome, display altered subcellular localization, or can suffer modifications on their interaction with functional protein complexes. Deregulation of E3 activities is frequently found in various human pathologies, including cancer. The illegitimated or accelerated degradation of oncosuppressive proteins or, inversely, the abnormally high accumulation of oncoproteins, contributes to cell proliferation and transformation. Anomalies in protein abundance may be related to mutations that alter the direct or indirect recognition of proteins by the E3 enzymes or alterations in the level of expression or activity of ubiquitin ligases. Through a few examples, we illustrate here the complexity and diversity of the molecular mechanisms related to protein ubiquitination involved in cell cycle regulation. We will discuss the role of ubiquitin-dependent degradation mediated by the proteasome, the role of non-proteolytic ubiquitination during cell cycle progression, and the consequences of this deregulation on cellular transformation. Finally, we will highlight the novel opportunities that arise from these studies for therapeutic intervention.
泛素连接酶（E3）通过空间和时间调节方式识别、相互作用和泛素化关键细胞蛋白，在调节细胞增殖和分化等不同细胞过程中发挥着关键作用。形成的泛素链的类型决定了底物的命运。被泛素化的底物可以被蛋白酶体降解，显示出改变的亚细胞定位，或者可以在其与功能蛋白复合物的相互作用上发生改变。E3 活性的失调在包括癌症在内的各种人类病理中经常被发现。肿瘤抑制蛋白的非法或加速降解，或者相反，癌蛋白的异常高积累，有助于细胞增殖和转化。蛋白质丰度的异常可能与改变 E3 酶直接或间接识别蛋白质的突变或泛素连接酶表达或活性水平的改变有关。通过几个例子，我们在这里说明了与细胞周期调控相关的蛋白质泛素化的分子机制的复杂性和多样性。我们将讨论由蛋白酶体介导的泛素依赖性降解的作用、细胞周期进程中非蛋白水解泛素化的作用，以及这种失调对细胞转化的影响。最后，我们将强调这些研究为治疗干预带来的新机会。
