Soond Surinder M, Savvateeva Lyudmila V, Makarov Vladimir A, Gorokhovets Neonila V, Townsend Paul A, Zamyatnin Andrey A
Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Str. 8-2, 119991 Moscow, Russia.
Division of Cancer Sciences and Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, and the NIHR Manchester Biomedical Research Centre, Manchester M13 9PL, UK.
Cancers (Basel). 2020 Nov 22;12(11):3476. doi: 10.3390/cancers12113476.
While viewed as the "guardian of the genome", the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic locus heavily implicated in a wide array of cancer types to modulating lysosomal-mediated cell death either directly or indirectly through the transcriptional regulation of the key signal transduction pathway intermediates involved in this. As an important step in determining the fate of cells in response to cytotoxicity or during stress response, lysosomal-mediated cell death has also become strongly interwoven with the key components that give the lysosome functionality in the form of the cathepsin proteases. While a number of articles have been published highlighting the independent input of p53 or cathepsins to cellular homeostasis and disease progression, one key area that warrants further focus is the regulatory relationship that p53 and its isoforms share with such proteases in regulating lysosomal-mediated cell death. Herein, we review recent developments that have shaped this relationship and highlight key areas that need further exploration to aid novel therapeutic design and intervention strategies.
尽管肿瘤抑制蛋白p53被视为“基因组守护者”，但其在调节与细胞死亡相关的其他作用方式方面的重要性日益得到更多认可。虽然进展缓慢但却确凿无疑，它的重要性已从一个与多种癌症类型密切相关的突变基因位点，发展到通过对参与其中的关键信号转导途径中间体进行转录调控，直接或间接调节溶酶体介导的细胞死亡。作为决定细胞在细胞毒性反应或应激反应中命运的重要一步，溶酶体介导的细胞死亡也与以组织蛋白酶形式赋予溶酶体功能的关键成分紧密交织在一起。虽然已经发表了许多文章强调p53或组织蛋白酶对细胞稳态和疾病进展的独立作用，但一个值得进一步关注的关键领域是p53及其异构体在调节溶酶体介导的细胞死亡中与这类蛋白酶的调控关系。在此，我们回顾了塑造这种关系的最新进展，并突出了需要进一步探索的关键领域，以助力新型治疗设计和干预策略。
