文章：

泛素连接酶：细胞周期控制与癌症

Ubiquitin ligases: cell-cycle control and cancer

原文发布日期：2006-05-01

DOI: 10.1038/nrc1881

类型: Review Article

开放获取: 否

要点：

1. Two major classes of ubiquitin ligases, the SKP1–CUL1–F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), have a central role in cell-cycle regulation.
2. The SCF complex and APC/C are structurally similar. Each is constituted of common subunits and a variable substrate-recognition subunit (F-box proteins for the SCF complex and activators for the APC/C). Three F-box proteins in the SCF complex — S-phase kinase-associated protein 2 (SKP2), F-box and WD-40 domain protein 7 (FBW7) and β-transducin repeat-containing protein (β-TRCP) — and two activators in the APC/C — cell division cycle 20 (CDC20) and CDH1 (also known as HCT1) — are the most important in cell-cycle regulation.
3. SKP2 targets negative regulators of the cell cycle such as p27, p21 and p57 for degradation, and thereby promotes cell-cycle progression during S and G2 phases. SKP2 is upregulated in many human cancers.
4. FBW7 induces the degradation of positive regulators of the cell cycle, such as MYC, JUN, cyclin E and Notch. FBW7 is often mutated in a subset of human cancers.
5. β-TRCP is a versatile F-box protein that recognizes several cell-cycle regulators — EMI1/2, WEE1A and CDC25A/B — in addition to its classical substrates, β-catenin and IκB. In some cancers, β-TRCP mutation or overexpression is found.
6. CDC20 targets securin and mitotic cyclins for destruction, and thereby promotes sister-chromatid separation. CDC20 is the crucial mediator of the spindle checkpoint, which prevents aneuploidy and genomic instability. CDC20 is overexpressed in some cancers, although in others the CDC20 gene is mutated or deleted.
7. CDH1 facilitates exit from M phase and maintains G1 phase by mediating the degradation of mitotic cyclins, non-CDK (cyclin-dependent kinase) mitotic kinases and some regulators of the formation of pre-replicative complexes. Deregulated expression or mutation of CDH1 as well as of most CDH1 targets have been described in human cancers.

要点翻译：

1. 两类主要的泛素连接酶——SKP1-CUL1-F-box蛋白（SCF）复合体和后期促进复合体/周期体（APC/C）——在细胞周期调控中发挥核心作用。
2. SCF复合体与APC/C在结构上相似，均由共同亚基和可变底物识别亚基（SCF复合体中的F-box蛋白和APC/C中的激活因子）构成。其中SCF复合体的三种F-box蛋白——S期激酶相关蛋白2（SKP2）、F-box及WD-40结构域蛋白7（FBW7）和β-转导素重复序列蛋白（β-TRCP），以及APC/C的两种激活因子——细胞分裂周期蛋白20（CDC20）和CDH1（亦称HCT1），在细胞周期调控中最为重要。
3. SKP2通过靶向降解p27、p21和p57等细胞周期负调控因子，促进S期和G2期的细胞周期进程。SKP2在多种人类癌症中表达上调。
4. FBW7可诱导MYC、JUN、细胞周期蛋白E和Notch等细胞周期正调控因子的降解。FBW7在部分人类癌症中常发生突变。
5. β-TRCP是一种多功能F-box蛋白，除经典底物β-连环蛋白和IκB外，还能识别EMI1/2、WEE1A和CDC25A/B等多种细胞周期调控因子。在某些癌症中发现存在β-TRCP突变或过表达。
6. CDC20通过靶向分离素和有丝分裂细胞周期蛋白进行降解，促进姐妹染色单体分离。作为纺锤体检查点的关键介质，CDC20可防止非整倍体和基因组不稳定性。虽然在某些癌症中CDC20基因存在突变或缺失，但在其他癌症中CDC20存在过表达。
7. CDH1通过介导有丝分裂细胞周期蛋白、非CDK（细胞周期蛋白依赖性激酶）有丝分裂激酶以及某些复制前复合体形成调控因子的降解，促进M期退出并维持G1期。在人类癌症中已发现CDH1及其多数靶标存在表达失调或突变。

英文摘要：

A driving force of the cell cycle is the activation of cyclin-dependent kinases (CDKs), the activities of which are controlled by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors. Two ubiquitin ligases, the SKP1–CUL1–F-box-protein (SCF) complex and the anaphase-promoting complex/cyclosome (APC/C), are responsible for the specific ubiquitylation of many of these regulators. Deregulation of the proteolytic system might result in uncontrolled proliferation, genomic instability and cancer. Cumulative clinical evidence shows alterations in the ubiquitylation of cell-cycle regulators in the aetiology of many human malignancies. A better understanding of the ubiquitylation machinery will provide new insights into the regulatory biology of cell-cycle transitions and the development of anti-cancer drugs.

摘要翻译： 

细胞周期的主要驱动力是细胞周期蛋白依赖性激酶（CDKs）的激活，其活性受到细胞周期蛋白和CDK抑制剂等关键调控因子通过泛素介导的蛋白降解的调控。两种泛素连接酶——SKP1–CUL1–F-box蛋白（SCF）复合物与后期促进复合物/周期体（APC/C）——负责这些调控因子的特异性泛素化。该蛋白水解系统的失调可能导致细胞不受控增殖、基因组不稳定及癌症。越来越多的临床证据表明，多种人类恶性肿瘤的发病机制中存在细胞周期调控因子泛素化的异常。深入理解泛素化机制将为揭示细胞周期转换的调控生物学及抗癌药物研发提供新视角。

原文链接：

Ubiquitin ligases: cell-cycle control and cancer