Functional analysis of Cullin 3 E3 ligases in tumorigenesis.
Functional analysis of Cullin 3 E3 ligases in tumorigenesis.
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DOI：
10.1016/j.bbcan.2017.11.001
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Cheng J;Guo J;Wang Z;North BJ;Tao K;Dai X;Wei W
Cullin 3-RING连接酶（CRL 3）在调节包括肿瘤事件在内的各种生理和病理过程中起关键作用。CRL 3的底物衔接子通常含有BTB结构域，其介导Cullin 3和靶底物之间的相互作用以促进其泛素化和随后的降解。已经很好地描述了CRL 3衔接蛋白的生物学意义，其中已经发现它们作为致癌基因、肿瘤抑制因子发挥作用，或者可以以上下文依赖的方式介导这些作用中的任一种。在广泛研究的基于CRL 3的E3连接酶中，衔接蛋白SPOP（斑点型BTB/POZ蛋白）在肿瘤发生中的作用似乎是组织或细胞环境依赖性的。具体而言，SPOP在许多恶性肿瘤中，特别是在前列腺癌中通过使下游癌蛋白不稳定而充当肿瘤抑制因子。然而，SPOP在肾癌中主要起致癌作用。Keap 1是另一种充分表征的CRL 3衔接蛋白，可能在多种恶性肿瘤中充当肿瘤抑制因子，主要是由于其下游致癌底物NRF 2（核因子红细胞2相关因子2）的特异性周转。根据各种CRL 3衔接子表现出的生理作用，已经开发了几种药理学试剂来破坏其E3连接酶活性，从而阻断其潜在的致癌活性以减轻肿瘤发生。
Cullin 3-RING ligases (CRL3) play pivotal roles in the regulation of various physiological and pathological processes, including neoplastic events. The substrate adaptors of CRL3 typically contain a BTB domain that mediates the interaction between Cullin 3 and target substrates to promote their ubiquitination and subsequent degradation. The biological implications of CRL3 adaptor proteins have been well described where they have been found to play a role as either an oncogene, tumor suppressor, or can mediate either of these effects in a context-dependent manner. Among the extensively studied CRL3-based E3 ligases, the role of the adaptor protein SPOP (speckle type BTB/POZ protein) in tumorigenesis appears to be tissue or cellular context dependent. Specifically, SPOP acts as a tumor suppressor via destabilizing downstream oncoproteins in many malignancies, especially in prostate cancer. However, SPOP has largely an oncogenic role in kidney cancer. Keap1, another well-characterized CRL3 adaptor protein, likely serves as a tumor suppressor within diverse malignancies, mainly due to its specific turnover of its downstream oncogenic substrate, NRF2 (nuclear factor erythroid 2-related factor 2). In accordance with the physiological role the various CRL3 adaptors exhibit, several pharmacological agents have been developed to disrupt its E3 ligase activity, therefore blocking its potential oncogenic activity to mitigate tumorigenesis.
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影响因子：
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