文章：

COP1在肿瘤发生中的作用

Spotlight on the role of COP1 in tumorigenesis

原文发布日期：2012-06-07

DOI: 10.1038/nrc3271

类型: Review Article

开放获取: 否

要点：

1. COP1 is a well-conserved E3 ubiquitin ligase that is involved in the ubiquitylation of various protein substrates to trigger their proteasomal degradation.
2. Several putative targets of mouse and human COP1 have been identified, including COP1 itself, p53, JUN and ETS variant (ETV) family members, indicating that depending on context it may act as an oncogene or as a tumour suppressor.
3. Both overexpression and loss of function of COP1 have been described in a variety of human tumours. In mice, the complete loss of COP1 function results in embryonic lethality, whereas studies of a partial loss of COP1 function have provided the first in vivo evidence for its tumour suppressor function.
4. Most identified COP1 targets are transcription factors that are implicated in cancer, although other targets imply that COP1 might also function in lipid and glucose metabolism. The main cellular functions of COP1 are probably mediated through the ubiquitylation and degradation of its substrates.
5. Unlike previously described E3 ligases, such as FBW7 and ITCH, COP1 can target unphosphorylated JUN for degradation. Thus, distinct pools of JUN may be targeted for degradation by different E3 ligases.
6. Given its role in the regulation of JUN and of the ETV family members, which are all known prostate cancer oncoproteins, COP1 might have a particularly important role in prostate cancer.
7. Despite early biochemical evidence that COP1 targets p53, recent in vivo data suggest that this interaction is unlikely to have an important role or to even occur in vivo.
8. The absence of confirmatory evidence for a role for COP1 in the regulation of p53 stability and activity argues against the use of COP1-inhibitory drugs for cancer therapy.

要点翻译：

1. COP1是一种高度保守的E3泛素连接酶，参与多种蛋白质底物的泛素化过程，从而触发其蛋白酶体降解。
2. 研究已鉴定出小鼠和人类COP1的若干潜在作用靶点，包括COP1自身、p53、JUN以及ETS变异（ETV）家族成员，这表明其功能具有环境依赖性，既可能作为癌基因也可能作为肿瘤抑制因子发挥作用。
3. 在多种人类肿瘤中，既观察到COP1的过表达现象，也发现其功能缺失的情况。小鼠模型中，COP1功能完全缺失会导致胚胎致死，而部分功能缺失的研究则首次为其肿瘤抑制功能提供了体内证据。
4. 大多数已鉴定的COP1靶点都是与癌症相关的转录因子，但其他靶点提示COP1可能在脂质和葡萄糖代谢中同样发挥作用。COP1的主要细胞功能很可能是通过介导底物的泛素化和降解来实现的。
5. 与先前描述的FBW7和ITCH等E3连接酶不同，COP1能够靶向未磷酸化的JUN进行降解。因此，不同亚群的JUN可能被不同的E3连接酶靶向降解。
6. 鉴于COP1在调控JUN和ETV家族成员（均为已知的前列腺癌癌蛋白）中的作用，该分子可能在前列腺癌中具有特别重要的意义。
7. 尽管早期生化证据表明COP1靶向p53，但近期体内研究数据显示这种相互作用在体内可能并不重要甚至不会发生。
8. 目前缺乏确凿证据证明COP1在调控p53稳定性及活性中发挥作用，因此不支持将COP1抑制药物用于癌症治疗。

英文摘要：

COP1 is an E3 ubiquitin ligase that is involved in the ubiquitylation of various protein substrates to trigger their proteasomal degradation. Although originally identified in a light signalling pathway in plants, biochemical studies have identified putative targets of mammalian COP1 with relevant roles in tumorigenesis, including the oncoproteins JUN and ETV family members, as well as the p53 tumour suppressor. Recent genetic studies have shown that COP1 deficiency leads to spontaneous tumour formation in mice, and have identified mutations in COP1 and its substrates in various human cancers. These findings add to our growing appreciation of the roles for E3 ligases in cancer.

摘要翻译： 

COP1是一种E3泛素连接酶，参与多种蛋白底物的泛素化过程，从而促进这些蛋白的蛋白酶体降解。尽管最初在植物的光信号通路中被发现，但生化研究已经鉴定出哺乳动物COP1的若干潜在靶标，这些靶标在肿瘤发生中具有重要作用，包括癌蛋白JUN和ETV家族成员，以及肿瘤抑制因子p53。近期遗传学研究表明，COP1缺失会导致小鼠自发形成肿瘤，并且在多种人类癌症中发现COP1及其底物的突变。这些发现进一步加深了我们对E3连接酶在癌症中作用的理解。

原文链接：

Spotlight on the role of COP1 in tumorigenesis