Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Biochim Biophys Acta Rev Cancer. 2018 Jan;1869(1):11-28. doi: 10.1016/j.bbcan.2017.11.001. Epub 2017 Nov 8.
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.
Cullin 3-RING 连接酶 (CRL3) 在调节各种生理和病理过程中发挥着关键作用，包括肿瘤发生事件。CRL3 的底物衔接子通常包含一个 BTB 结构域，该结构域介导 Cullin 3 与靶底物之间的相互作用，促进它们的泛素化和随后的降解。CRL3 衔接蛋白的生物学意义已经得到了很好的描述，它们被发现作为癌基因、肿瘤抑制因子发挥作用，或者在依赖于上下文的情况下介导这两种效应。在广泛研究的基于 CRL3 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依赖于组织或细胞的上下文。具体来说，SPOP 通过在许多恶性肿瘤中（尤其是前列腺癌）使下游癌蛋白不稳定而充当肿瘤抑制因子。然而，SPOP 在肾癌中主要发挥致癌作用。另一种经过充分研究的 CRL3 衔接蛋白 Keap1 可能在多种恶性肿瘤中作为肿瘤抑制因子发挥作用，主要是由于其对下游致癌底物 NRF2（核因子红细胞 2 相关因子 2）的特异性降解。根据各种 CRL3 衔接蛋白表现出的生理作用，已经开发了几种药理学药物来破坏其 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。
