文章：

FBW7泛素连接酶：细胞分裂、生长和分化十字路口的肿瘤抑制因子

FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation

原文发布日期：2008-02-01

DOI: 10.1038/nrc2290

类型: Review Article

开放获取: 否

要点：

1. SCF (complex of SKP1, CUL1 and F-box protein) complexes are ubiquitin ligases that bind to protein substrates and target them for ubiquitylation and subsequent degradation by the proteasome. F-box proteins are the SCF components that recognize specific protein substrates.
2. FBW7 (F-box and WD repeat domain-containing 7) is an F-box protein that binds to key regulators of cell division and growth, including cyclin E, MYC, JUN and Notch. Most FBW7 substrates are proto-oncogenes that are broadly implicated in the pathogenesis of human cancers.
3. FBW7 binds to its substrates after they have been phosphorylated within conserved phospho-degron motifs, called CPDs (Cdc4 phospho-degrons). Substrate phosphorylation is highly regulated. Most substrates are phosphorylated within their CPDs by glycogen synthase kinase 3, a mitogen regulated kinase, and CPDs couple FBW7 activity with mitogenic signalling pathways.
4. FBW7 is a tumour suppressor, and loss of FBW7 function leads to chromosomal instability, probably owing to hyperactivation of its many oncogenic substrates.
5. Mutations in FBW7 occur in diverse human malignancies. FBW7 exhibits an unusual mutational spectrum in tumours, and different types of mutation can have substrate-specific consequences, including dominant-negative effects. Mutations within substrate CPDs are also found in tumours, and provide another mechanism for the oncogenic substrates of FBW7 to evade destruction.

要点翻译：

1. SCF（由SKP1、CUL1和F-box蛋白组成的复合物）复合体是一类泛素连接酶，能够结合蛋白质底物并靶向引导其发生泛素化，随后被蛋白酶体降解。F-box蛋白作为SCF复合体的识别组分，负责特异性识别蛋白质底物。
2. FBW7（含F-box与WD重复结构域蛋白7）是一种F-box蛋白，可结合细胞分裂与生长的关键调控因子，包括细胞周期蛋白E、MYC、JUN和Notch。大多数FBW7底物为原癌基因，广泛参与人类癌症的发病机制。
3. FBW7在其底物保守磷酸降解基序（称为CPD，即Cdc4磷酸降解子）发生磷酸化后与之结合。底物磷酸化过程受到严格调控，多数底物的CPD区域由糖原合成酶激酶3（一种有丝分裂调控激酶）催化磷酸化，CPD将FBW7活性与有丝分裂信号通路相偶联。
4. FBW7是一种肿瘤抑制因子，其功能缺失会导致染色体不稳定性，这很可能源于其多种致癌底物的过度激活。
5. FBW7突变见于多种人类恶性肿瘤。该基因在肿瘤中呈现特殊的突变谱，不同类型的突变可能对底物产生特异性影响，包括显性负效应。肿瘤中也发现底物CPD区域的突变，这为FBW7的致癌底物逃避降解提供了另一种机制。

英文摘要：

FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCFFBW7 degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer.

摘要翻译： 

FBW7（含F-box和WD重复结构域蛋白7）是进化上保守的SCF型泛素连接酶（SKP1-CUL1-F-box蛋白复合体）中的底物识别亚基。SCF^FBW7可降解多条细胞生长与分裂通路中的若干原癌蛋白，包括MYC、细胞周期蛋白E、Notch和JUN。FBW7亦为一种肿瘤抑制因子，其调控网络在多种人类恶性肿瘤中受到干扰。研究已发现大量与癌症相关的FBW7及其底物突变，FBW7功能缺失会导致染色体不稳定和肿瘤发生。本综述聚焦于FBW7的结构与功能特点，以及其在癌症发展中的作用。

原文链接：

FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation