文章：

善与恶的环：环指泛素连接酶在肿瘤抑制和肿瘤发生的十字路口

RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis

原文发布日期：2011-08-24

DOI: 10.1038/nrc3120

类型: Review Article

开放获取: 否

要点：

1. RING finger ubiquitin-protein ligases (E3s) are the most abundant class of E3 that mediate protein ubiquitylation (also known as ubiquitination). They regulate crucial cellular functions, such as the cell cycle, DNA repair, cell signalling and responses to hypoxia. Genetic alterations, including activating and inactivating mutations, gene amplifications, translocations and deletions, have been described for many RING finger E3s. RING finger E3s are validated oncogenes (such as MDM2) or tumour suppressor genes (such as BRCA1 and von Hippel–Lindau tumour suppressor (VHL)) because of their role in regulating crucial cell functions.
2. The cell cycle is regulated by the S phase kinase-associated protein 1 (SKP1)–cullin 1 (CUL1)–F-box protein (SCF) and anaphase-promoting complex/cyclosome (APC/C) multisubunit RING finger E3s. These complexes are targeted to specific substrates via interchangeable substrate recognition subunits, including F-box proteins for SCF and cell division cycle 20 (CDC20) and CDH1 for APC/C. These multisubunit E3s have a large number of substrates with oncogenic and tumour suppressive effects. Genetic alterations to components of these E3 complexes that result in loss of function (such as FBW7, CDH1 and CDC20) or gain of function (such as SKP2 and β-transducin repeat-containing protein (β-TrCP)) are implicated in the development of cancer.
3. RING finger E3s have central roles in DNA damage responses and DNA repair. For example, MDM2 targets p53 for degradation. MDM2 is amplified, overexpressed or activated in other ways in cancers and is a means of inactivating the tumour suppressor p53. The BRCA1 and the Fanconi anaemia (FANC) E3s have essential roles in the repair of DNA damage; both E3s function as tumour suppressors.
4. RING finger E3s have important roles in both positively and negatively regulating signal transduction. A prominent example of negative regulation is the CBL family of RING finger E3s that target activated receptor tyrosine kinases (RTKs) for degradation. Mutations that inactivate CBL E3 function have been described in myeloid neoplasms and result in the hyperactivation of RTKs and intracellular signalling pathways.
5. The response to hypoxia is regulated by the multisubunit CRL2^VHL RING finger E3 and the single subunit RING finger E3 SIAH. The VHL complex targets the hypoxia-inducible factor-α (HIFα) transcription factors for proteasomal degradation, which prevents the expression of angiogenic and growth-promoting genes under normoxic conditions. Inactivating mutations of VHL are found in familial and sporadic clear cell cancer of the kidney, resulting in the stabilization of the HIFα transcription factor subunits and consequently abnormally high expression of angiogenic and growth genes. By contrast, the SIAH RING finger E3s stabilize HIFα under hypoxic conditions.
6. Targeting RING finger E3s for the treatment of cancer is being actively explored. For example, small-molecule inhibitors have been developed that interfere with the MDM2–p53 interaction or that inhibit MDM2 E3 activity, thus stabilizing p53. These approaches have demonstrated antitumour activity in preclinical studies, but the clinical efficacy of interfering with MDM2 function remains to be determined. Targeting the loss of activity of RING finger E3s that are tumour suppressors will require novel approaches such as the synthetic lethality that is induced by poly(ADP-ribose) polymerase (PARP) inhibition in cells that are deficient in BRCA1 or BRCA2.

要点翻译：

1. RING指状结构泛素-蛋白连接酶（E3s）是介导蛋白质泛素化（也称为泛素化）的最丰富的一类E3。它们调控关键的细胞功能，如细胞周期、DNA修复、细胞信号传导以及对缺氧的反应。许多RING指状结构E3s已被报道存在遗传改变，包括激活和失活突变、基因扩增、易位和缺失。由于其在调控关键细胞功能中的作用，RING指状结构E3s被证实为癌基因（如MDM2）或肿瘤抑制基因（如BRCA1和von Hippel-Lindau肿瘤抑制因子（VHL））。
2. 细胞周期由S期激酶相关蛋白1（SKP1）-Cullin 1（CUL1）-F-box蛋白（SCF）和后期促进复合物/周期体（APC/C）多亚基RING指状结构E3s调控。这些复合物通过可互换的底物识别亚单位靶向特定底物，包括SCF的F-box蛋白以及APC/C的细胞分裂周期20（CDC20）和CDH1。这些多亚基E3s具有大量具有致癌和肿瘤抑制效应的底物。这些E3复合物组分的遗传改变导致功能丧失（如FBW7、CDH1和CDC20）或功能获得（如SKP2和含β-转导蛋白重复序列蛋白（β-TrCP））与癌症的发生有关。
3. RING指状结构E3s在DNA损伤反应和DNA修复中起核心作用。例如，MDM2靶向p53进行降解。MDM2在癌症中被扩增、过表达或以其他方式激活，是使肿瘤抑制因子p53失活的一种手段。BRCA1和范可尼贫血（FANC）E3s在DNA损伤修复中具有重要作用；这两种E3s均作为肿瘤抑制因子发挥作用。
4. RING指状结构E3s在正向和负向调控信号转导中均具有重要作用。负向调控的一个突出例子是CBL家族的RING指状结构E3s，它们靶向活化的受体酪氨酸激酶（RTKs）进行降解。在骨髓性肿瘤中已报道了使CBL E3功能失活的突变，这些突变导致RTKs和细胞内信号通路的过度激活。
5. 对缺氧的反应由多亚基CRL2VHL RING指状结构E3和单亚基RING指状结构E3 SIAH调控。VHL复合物靶向低氧诱导因子-α（HIFα）转录因子进行蛋白酶体降解，从而在常氧条件下阻止血管生成和促生长基因的表达。在家族性和散发性肾透明细胞癌中发现VHL的失活突变，导致HIFα转录因子亚基的稳定，从而异常高表达血管生成和生长基因。相比之下，SIAH RING指状结构E3s在缺氧条件下稳定HIFα。
6. 针对RING指状结构E3s以治疗癌症的研究正在积极进行中。例如，已开发出小分子抑制剂干扰MDM2-p53相互作用或抑制MDM2 E3活性，从而稳定p53。这些方法在临床前研究中已显示出抗肿瘤活性，但干扰MDM2功能的临床疗效仍有待确定。针对作为肿瘤抑制因子的RING指状结构E3s活性丧失的治疗将需要新方法，例如在BRCA1或BRCA2缺陷的细胞中通过聚（ADP-核糖）聚合酶（PARP）抑制诱导的合成致死性。

英文摘要：

The ubiquitin-proteasome system has numerous crucial roles in physiology and pathophysiology. Fundamental to the specificity of this system are ubiquitin-protein ligases (E3s). Of these, the majority are RING finger and RING finger-related E3s. Many RING finger E3s have roles in processes that are central to the maintenance of genomic integrity and cellular homeostasis, such as the anaphase promoting complex/cyclosome (APC/C), the SKP1–cullin 1–F-box protein (SCF) E3s, MDM2, BRCA1, Fanconi anaemia proteins, CBL proteins, von Hippel–Lindau tumour suppressor (VHL) and SIAH proteins. As a result, many RING finger E3s are implicated in either the suppression or the progression of cancer. This Review summarizes current knowledge in this area.

摘要翻译： 

泛素-蛋白酶体系统在生理学和病理生理学中具有许多关键作用。该系统的特异性根本上依赖于泛素蛋白连接酶（E3）。其中，大多数为RING指和RING指相关E3。许多RING指E3在维持基因组完整性和细胞稳态的核心过程中发挥作用，例如后期促进复合体/环体（APC/C）、SKP1–cullin 1–F-box蛋白（SCF）E3、MDM2、BRCA1、范可尼贫血蛋白、CBL蛋白、von Hippel–Lindau肿瘤抑制因子（VHL）和SIAH蛋白。因此，许多RING指E3与癌症的抑制或进展有关。本综述总结了该领域的当前知识。

原文链接：

RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis