Department of Large Animal Diseases and Clinic, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 100 Nowoursynowska St., 02-797 Warsaw, Poland.
Int J Mol Sci. 2020 Feb 17;21(4):1334. doi: 10.3390/ijms21041334.
Forty years of research has proven beyond any doubt that p53 is a key regulator of many aspects of cellular physiology. It is best known for its tumor suppressor function, but it is also a regulator of processes important for maintenance of homeostasis and stress response. Its activity is generally antiproliferative and when the cell is damaged beyond repair or intensely stressed the p53 protein contributes to apoptosis. Given its key role in preventing cancer it is no wonder that it is the most frequently mutated gene in human cancer. Surprisingly, a subset of missense mutations occurring in p53 (gain-of-function) cause it to lose its suppressor activity and acquire new functionalities that turn the tumor suppressor protein into an oncoprotein. A solid body of evidence exists demonstrating increased malignancy of cancers with mutated p53 in all aspects considered "hallmarks of cancer". In this review, we summarize current findings concerning the cellular processes altered by gain-of-function mutations in p53 and their influence on cancer invasiveness and metastasis. We also present the variety of molecular mechanisms regulating these processes, including microRNA, direct transcriptional regulation, protein-protein interactions, and more.
四十年的研究无可置疑地证明，p53 是细胞生理多方面的关键调节因子。它最广为人知的功能是作为肿瘤抑制因子，但它也是维持内稳态和应激反应的重要过程的调节剂。它的活性通常具有抗增殖作用，当细胞受损无法修复或受到强烈压力时，p53 蛋白会促进细胞凋亡。鉴于其在预防癌症方面的关键作用，p53 是人类癌症中最常发生突变的基因也就不足为奇了。令人惊讶的是，p53 中发生的一小部分错义突变（获得功能）导致其失去抑制活性，并获得新的功能，将肿瘤抑制蛋白转化为癌蛋白。大量证据表明，在所有被认为是“癌症特征”的方面，带有突变 p53 的癌症的恶性程度都有所增加。在这篇综述中，我们总结了目前关于 p53 获得功能突变改变的细胞过程及其对癌症侵袭和转移的影响的研究结果。我们还介绍了调节这些过程的多种分子机制，包括 microRNA、直接转录调控、蛋白-蛋白相互作用等。
