Pan Mengwu, Blattner Christine
Institute of Biological and Chemical Systems-Biological Information Processing, Karlsruhe Institute of Technology, PO-box 3640, 76021 Karlsruhe, Germany.
Cancers (Basel). 2021 Feb 11;13(4):745. doi: 10.3390/cancers13040745.
More than 40 years of research on p53 have given us tremendous knowledge about this protein. Today we know that p53 plays a role in different biological processes such as proliferation, invasion, pluripotency, metabolism, cell cycle control, ROS (reactive oxygen species) production, apoptosis, inflammation and autophagy. In the nucleus, p53 functions as a bona-fide transcription factor which activates and represses transcription of a number of target genes. In the cytoplasm, p53 can interact with proteins of the apoptotic machinery and by this also induces cell death. Despite being so important for the fate of the cell, expression levels of p53 are kept low in unstressed cells and the protein is largely inactive. The reason for the low expression level is that p53 is efficiently degraded by the ubiquitin-proteasome system and the vast inactivity of the tumor suppressor protein under normal growth conditions is due to the absence of activating and the presence of inactivating posttranslational modifications. E3s are important enzymes for these processes as they decorate p53 with ubiquitin and small ubiquitin-like proteins and by this control p53 degradation, stability and its subcellular localization. In this review, we provide an overview about E3s that target p53 and discuss the connection between p53, E3s and tumorigenesis.
40 多年来对 p53 的研究让我们对这种蛋白质有了极为丰富的认识。如今我们知道，p53 在不同的生物学过程中发挥作用，如增殖、侵袭、多能性、代谢、细胞周期调控、活性氧（ROS）生成、细胞凋亡、炎症和自噬。在细胞核中，p53 作为一种真正的转录因子发挥作用，激活和抑制许多靶基因的转录。在细胞质中，p53 可与凋亡机制的蛋白质相互作用，进而诱导细胞死亡。尽管 p53 对细胞命运至关重要，但在未受应激的细胞中其表达水平保持较低，且该蛋白质在很大程度上处于无活性状态。其表达水平低的原因是 p53 被泛素 - 蛋白酶体系统有效降解，而在正常生长条件下这种肿瘤抑制蛋白的大量无活性状态是由于缺乏激活的翻译后修饰以及存在失活的翻译后修饰。E3 酶是这些过程中的重要酶，因为它们用泛素和类泛素小蛋白修饰 p53，从而控制 p53 的降解、稳定性及其亚细胞定位。在这篇综述中，我们概述了靶向 p53 的 E3 酶，并讨论了 p53、E3 酶与肿瘤发生之间的联系。
