Could Dysregulation of UPS be a Common Underlying Mechanism for Cancer and Neurodegeneration? Lessons from UCHL1
Could Dysregulation of UPS be a Common Underlying Mechanism for Cancer and Neurodegeneration? Lessons from UCHL1
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DOI：
10.1007/s12013-013-9631-7
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发表时间：
2013-09-01
影响因子：
2.6
通讯作者：
Oezdinler, P. Hande
中科院分区：
文献类型：
--
作者：
Jara, Javier H.;Frank, Dominic D.;Oezdinler, P. Hande
泛素蛋白酶体系统（Ubiquitin proteasome system， UPS）决定着细胞中蛋白质转换的时间和程度，是最受严格控制的细胞机制之一。缺乏对UPS的适当控制可归因于癌症和神经退行性疾病，但在不同的背景和方向。癌细胞改变了细胞代谢，细胞分裂失控，蛋白酶体活性增加。这种特殊的功能阻止神经元进行细胞分裂，但允许它们在很远的距离上延伸轴突，建立连接，并形成稳定的神经回路。神经元在很大程度上依赖于蛋白酶体和UPS的正常功能。易损神经元中UPS功能的降低导致蛋白质聚集、内质网应激增加和细胞死亡。在不同的恶性肿瘤中选择性阻断蛋白酶体功能的化合物的鉴定增加了药物发现的动力，去泛素酶（DUBs）得到了广泛的关注。本文将重点讨论泛素羧基末端水解酶L1 (UCHL1)，这是一种与癌症和神经变性有关的DUB。通过控制UPS的功能为两个主要健康问题制定有效治疗战略的潜力为创新方法和治疗干预开辟了新的途径。
Ubiquitin proteasome system (UPS) determines the timing and extent of protein turnover in cells, and it is one of the most strictly controlled cellular mechanisms. Lack of proper control over UPS is attributed to both cancer and to neurodegenerative diseases, yet in different context and direction. Cancerous cells have altered cellular metabolisms, uncontrolled cellular division, and increased proteasome activity. The specialized function prevent neurons from undergoing cellular division but allow them to extend an axon over long distances, establish connections, and to form stable neuronal circuitries. Neurons heavily depend on the proper function of the proteasome and the UPS for their proper function. Reduction of UPS function in vulnerable neurons results in protein aggregation, increased ER stress, and cell death. Identification of compounds that selectively block proteasome function in distinct set of malignancies added momentum to drug discovery efforts, and deubiquitinases (DUBs) gained much attention. This review will focus on ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a DUB that is attributed to both cancer and neurodegeneration. The potential of developing effective treatment strategies for two major health problems by controlling the function of UPS opens up new avenues for innovative approaches and therapeutic interventions.