文章：

F-box蛋白在癌症中的作用

Roles of F-box proteins in cancer

原文发布日期：2014-03-24

DOI: 10.1038/nrc3700

类型: Review Article

开放获取: 否

要点：

1. F-box proteins have pivotal roles in the development and progression of human malignancies through governing the turnover of key factors that are involved in multiple cellular processes, including cell proliferation, apoptosis, invasion, angiogenesis and metastasis.
2. In order to determine the possible role for each of the 69 identified mammalian F-box proteins in tumorigenesis, we focused on summarizing experimental evidence derived from physiological mouse models, pathological gene alterations in cancer patients and biochemical substrates identified for respective F-box proteins.
3. F-box/WD repeat-containing protein 7 (FBXW7) exerts its tumour-suppressor role mostly by promoting the degradation of various oncoproteins that regulate important cellular processes including cell cycle progression, cellular metabolism, differentiation and apoptosis. Moreover, FBXW7 somatic mutations have been observed in various human cancers, and genetic ablation of Fbxw7 in different tissue settings predisposes mice to cancer.
4. S-phase kinase-associated protein 2 (SKP2) promotes tumorigenesis mostly by promoting the ubiquitylation and subsequent degradation of a cohort of tumour-suppressor proteins, including p27, p21, p130 and forkhead box protein O1 (FOXO1). Skp2 transgenic mouse models, and overexpression of SKP2 in various types of human cancers further support a role for SKP2 as a proto-oncoprotein.
5. β-transducin repeat-containing protein 1 (β-TRCP1) and β-TRCP2 exert their oncogenic or tumour-suppressive function in a tissue-specific, or cellular context-dependent manner.
6. For a subset of F-box proteins with emerging oncogenic or tumour-suppressive roles, genetic mouse models have been established to shed light on the potential role of these proteins in tumorigenesis. However, further additional compound or tissue-specific mouse models, as well as identification of downstream substrates, are necessary to clearly define the roles of these proteins in cancer.
7. F-box proteins with undetermined roles in tumorigenesis are defined for those members without studies from cancerous mouse models, although pathological genetic alterations or characterized tumour-associated substrates might have provided minimal support for their possible involvement in tumorigenesis.
8. Targeting F-box proteins, or F-box protein signalling pathways, could be an effective strategy for prevention or treatment of human cancers.

要点翻译：

1. F-box蛋白通过调控多种细胞过程（包括细胞增殖、凋亡、侵袭、血管生成和转移）中关键因子的周转，在人类恶性肿瘤的发生发展中起核心作用。
2. 为确定69种已鉴定哺乳动物F-box蛋白在肿瘤发生中的潜在作用，我们着重总结了来自生理小鼠模型的实验证据、癌症患者的病理基因改变以及各F-box蛋白已鉴定的生化底物。
3. F-box/WD重复结构域蛋白7（FBXW7）主要通过促进调控重要细胞过程（如细胞周期进程、细胞代谢、分化和凋亡）的多种癌蛋白降解来发挥其肿瘤抑制功能。此外，在多种人类癌症中观察到FBXW7体细胞突变，且不同组织环境中Fbxw7的基因缺失会使小鼠易患癌症。
4. S期激酶相关蛋白2（SKP2）主要通过促进包括p27、p21、p130和叉头框蛋白O1（FOXO1）在内的一组肿瘤抑制蛋白的泛素化及后续降解来促进肿瘤发生。Skp2转基因小鼠模型以及SKP2在多种人类癌症中的过表达进一步支持SKP2作为原癌蛋白的作用。
5. β-转导重复序列包含蛋白1（β-TRCP1）和β-TRCP2以组织特异性或细胞环境依赖的方式发挥其促癌或抑癌功能。
6. 对于具有新兴促癌或抑癌作用的F-box蛋白亚群，已建立遗传小鼠模型以揭示这些蛋白在肿瘤发生中的潜在作用。然而，需要进一步构建复合性或组织特异性小鼠模型并鉴定下游底物，以明确这些蛋白在癌症中的作用。
7. 对于尚未通过癌症小鼠模型进行研究的部分F-box蛋白成员，其在肿瘤发生中的作用尚未明确——尽管病理性遗传改变或已表征的肿瘤相关底物可能为其参与肿瘤发生提供了初步支持依据。
8. 靶向F-box蛋白或其信号通路可能成为预防和治疗人类癌症的有效策略。

英文摘要：

F-box proteins, which are the substrate-recognition subunits of SKP1–cullin 1–F-box protein (SCF) E3 ligase complexes, have pivotal roles in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins. Dysregulation of F-box protein-mediated proteolysis leads to human malignancies. Notably, inhibitors that target F-box proteins have shown promising therapeutic potential, urging us to review the current understanding of how F-box proteins contribute to tumorigenesis. As the physiological functions for many of the 69 putative F-box proteins remain elusive, additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F-box protein-targeted anticancer therapies.

摘要翻译： 

F-box蛋白是SKP1–cullin 1–F-box蛋白（SCF）E3泛素连接酶复合体的底物识别亚基，通过泛素化并降解靶蛋白，在多种细胞过程中发挥关键作用。F-box蛋白介导的蛋白降解失调会导致人类恶性肿瘤。值得注意的是，靶向F-box蛋白的抑制剂已显示出良好的治疗潜力，促使我们回顾目前对F-box蛋白在肿瘤发生中作用的理解。由于69个假定F-box蛋白中许多蛋白的生理功能尚不清楚，进一步的遗传学和机制研究将有助于明确每个F-box蛋白在肿瘤发生中的作用，从而为合理设计靶向F-box蛋白的抗癌疗法铺平道路。

原文链接：

Roles of F-box proteins in cancer