Dissenting degradation: Deubiquitinases in cell cycle and cancer.
Dissenting degradation: Deubiquitinases in cell cycle and cancer.
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DOI：
10.1016/j.semcancer.2020.03.008
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发表时间：
2020-12
影响因子：
14.5
通讯作者：
Emanuele MJ
中科院分区：
文献类型：
--
作者：
Bonacci T;Emanuele MJ
自四十年前被发现以来，蛋白质泛素化一直是一个不断扩展的领域。事实上，所有生物过程都是由泛素与靶蛋白的翻译后缀合控制的。此外，由于泛素通过数百种酶的作用控制底物降解，其中许多酶代表了有吸引力的治疗候选者，因此利用泛素系统重塑蛋白质组为改善疾病结果带来了巨大希望。在泛素控制的众多生理功能中，细胞周期是最关键的之一。事实上，细胞周期进程的关键驱动因素受泛素蛋白酶体系统 (UPS) 调节这一发现集中体现了泛素信号传导与增殖之间的联系。由于癌症是一种细胞周期进展和增殖失控的疾病，因此靶向 UPS 来阻止癌细胞周期和增殖具有巨大的治疗潜力。泛素化是可逆的，泛素通过称为去泛素酶或 DUB 的催化蛋白酶从底物上去除。虽然泛素化与增殖和癌症密切相关，但 DUB 的作用代表了这一领域的一层复杂性，但目前人们对它的了解还很有限。由于 DUB 能够通过改变蛋白质降解动力学来重塑蛋白质组，因此它们在正常细胞和癌细胞的细胞周期和增殖中发挥着重要但未被充分认识的作用。此外，由于它们的酶促蛋白酶活性和开放的泛素结合袋，DUB 可能在未来的癌症治疗中发挥重要作用，因为它们是 UPS 中最容易成药的酶之一。在这篇综述中，我们总结了将 DUB 与细胞周期和增殖以及癌症的病因学和治疗联系起来的新的重要发现。我们还强调了开发攻击 DUB 以获得治疗效果的药理学方法的新进展。
Since its discovery forty years ago, protein ubiquitination has been an ever-expanding field. Virtually all biological processes are controlled by the post-translational conjugation of ubiquitin onto target proteins. In addition, since ubiquitin controls substrate degradation through the action of hundreds of enzymes, many of which represent attractive therapeutic candidates, harnessing the ubiquitin system to reshape proteomes holds great promise for improving disease outcomes. Among the numerous physiological functions controlled by ubiquitin, the cell cycle is among the most critical. Indeed, the discovery that the key drivers of cell cycle progression are regulated by the ubiquitin-proteasome system (UPS) epitomizes the connection between ubiquitin signaling and proliferation. Since cancer is a disease of uncontrolled cell cycle progression and proliferation, targeting the UPS to stop cancer cells from cycling and proliferating holds enormous therapeutic potential. Ubiquitination is reversible, and ubiquitin is removed from substrates by catalytic proteases termed deubiquitinases or DUBs. While ubiquitination is tightly linked to proliferation and cancer, the role of DUBs represents a layer of complexity in this landscape that remains poorly captured. Due to their ability to remodel the proteome by altering protein degradation dynamics, DUBs play an important and underappreciated role in the cell cycle and proliferation of both normal and cancer cells. Moreover, due to their enzymatic protease activity and an open ubiquitin binding pocket, DUBs are likely to be important in the future of cancer treatment, since they are among the most druggable enzymes in the UPS. In this review, we summarize new and important findings linking DUBs to cell cycle and proliferation, as well as to the etiology and treatment of cancer. We also highlight new advances in developing pharmacological approaches to attack DUBs for therapeutic benefit.
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影响因子：
11.2
作者：
Chernikova SB;Razorenova OV;Higgins JP;Sishc BJ;Nicolau M;Dorth JA;Chernikova DA;Kwok S;Brooks JD;Bailey SM;Game JC;Brown JM
通讯作者：
Brown JM
影响因子：
4.8
作者：
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通讯作者：
Grant, PA
影响因子：
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作者：
Brummelkamp, TR;Nijman, SMB;Bernards, R
通讯作者：
Bernards, R
影响因子：
64.8
作者：
Bashir, T;Dorrello, NV;Pagano, M
通讯作者：
Pagano, M
影响因子：
4.8
作者：
Cohen, M;Stutz, F;Dargemont, C
通讯作者：
Dargemont, C