Proteasome-associated deubiquitinases and cancer.
Proteasome-associated deubiquitinases and cancer.
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DOI：
10.1007/s10555-017-9697-6
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
D'Arcy P
中科院分区：
文献类型：
--
作者：
Mofers A;Pellegrini P;Linder S;D'Arcy P
维持蛋白质的动态平衡是细胞正常运作的关键过程。蛋白质的调节降解主要由泛素蛋白酶体系统(UPS)促进，UPS是一种用泛素选择性标记蛋白质的系统，然后由蛋白酶体介导的蛋白降解。UPS是高度动态的，由调节蛋白质稳定和降解的泛素化和去泛素化步骤组成。蛋白质稳定性的失调是许多癌症类型发生和发展的共同特征。与此同时，癌细胞蛋白质合成率的提高以及随之而来的错误折叠蛋白质的积累促使UPS上瘾，从而使它们对UPS抑制剂敏感。这种敏感性以及稳定促凋亡信号通路的潜力使蛋白酶体成为开发新疗法的一个有吸引力的临床靶点。靶向蛋白酶体的催化20S亚单位已经是多发性骨髓瘤和其他癌症的临床验证策略。在这一成功的推动下，前景看好的UPS新型抑制剂已经进入开发阶段，目标是20年代以及调节19年代的脱泛素化和泛素连接酶的亚单位和抑制剂。在这篇综述中，我们概述了UPS放松调控导致癌症发生的方式，蛋白酶体抑制剂的临床应用现状，以及UPS新型抑制剂的(临床前)开发。
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
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影响因子：
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作者：
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DOI：
10.1158/1078-0432.ccr-12-3696
发表时间：
2013-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Byun S;Lee SY;Lee J;Jeong CH;Farrand L;Lim S;Reddy K;Kim JY;Lee MH;Lee HJ;Bode AM;Won Lee K;Dong Z
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