文章：

F-box蛋白SKP2和β-TrCP的不受调节的蛋白水解：癌症的天平倾斜

Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer

原文发布日期：2008-06-01

DOI: 10.1038/nrc2396

类型: Review Article

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要点：

1. Targeted protein proteolysis of key regulatory proteins by the ubiquitin–proteasome system (UPS) has a central role in maintaining and regulating growth. As such, components of the UPS can promote or prevent cellular transformation, which results from an aberrant response to otherwise normal cues that regulate processes involved in proliferation, differentiation and apoptosis.
2. The SCF (SKP1–CUL1–F-box protein) ubiquitin ligases are the best characterized mammalian cullin RING ubiquitin ligases, and the F-box protein provides the substrate targeting specificity of the complex.
3. Out of sixty-nine F-box proteins that have been identified in humans, only nine have been matched with their respective substrates. The F-box proteins SKP2 (S-phase kinase-associated protein 2) and β-TrCP (β-transducin repeat-containing protein) have emerged as key regulatory molecules with roles in cellular processes that are intimately related to tumorigenesis.
4. SKP2 is an oncogenic protein that targets tumour suppressor proteins for degradation. As a positive regulator of cell cycle progression, a major target of SKP2 is the cyclin-dependent kinase (CDK) inhibitor p27, as has been shown in vivo and in vitro. Increased levels of SKP2 and reduced levels of p27 are observed in many types of cancer, and these levels are in several cases used as independent prognostic markers.
5. Whereas β-TrCP has been previously suggested to possess both oncogenic and tumour suppressive characteristics — mainly owing to the diversity in β-TrCP substrates — recent evidence indicates β-TrCP is mainly oncogenic.
6. Previous attempts at targeting components of the degradation machinery have been successful for laboratory and clinical use, as observed in the effectiveness of the proteasome inhibitor bortezomib (Velcade) in multiple myeloma. The development of pharmaceutical compounds targeting specific SCF ubiquitin ligases is timely and is complemented by structural and basic biochemical studies that have identified substrates for important cellular regulators such as SKP2 and β-TrCP.

要点翻译：

1. 泛素-蛋白酶体系统（UPS）通过对关键调控蛋白进行靶向蛋白质水解，在维持和调控生长中发挥核心作用。因此，UPS的组分可以促进或阻止细胞转化，这种转化源于细胞对正常调控信号的异常反应，这些信号本应调节增殖、分化和凋亡相关过程。
2. SCF（SKP1-CUL1-F-box蛋白）泛素连接酶是特征最明确的哺乳动物cullin RING泛素连接酶，其中F-box蛋白为复合物提供了底物靶向特异性。
3. 在人类已鉴定的69种F-box蛋白中，仅9种与其相应底物得到匹配。F-box蛋白SKP2（S期激酶相关蛋白2）和β-TrCP（含β-转导蛋白重复序列蛋白）已成为关键调控分子，在与肿瘤发生密切相关的细胞过程中发挥作用。
4. SKP2是一种靶向降解肿瘤抑制蛋白的致癌蛋白。作为细胞周期进程的正向调控因子，SKP2主要靶标是细胞周期蛋白依赖性激酶（CDK）抑制剂p27，这在体内和体外实验中均得到证实。在许多癌症类型中观察到SKP2水平升高和p27水平降低，这些指标在若干情况下被用作独立的预后标志物。
5. 尽管β-TrCP先前被认为同时具有致癌和肿瘤抑制特性——这主要归因于其底物的多样性——但最新证据表明β-TrCP主要发挥致癌作用。
6. 正如蛋白酶体抑制剂硼替佐米（万珂）在多发性骨髓瘤中的疗效所示，此前针对降解机制组分的靶向尝试已在实验室和临床应用中取得成功。针对特定SCF泛素连接酶的药物化合物开发正当时，且与结构生物学及基础生化研究形成互补——这些研究已鉴定出SKP2和β-TrCP等重要细胞调控因子的作用底物。

英文摘要：

The maintenance and preservation of distinct phases during the cell cycle is a highly complex and coordinated process. It is regulated by phosphorylation — through the activity of cyclin-dependent kinases (CDKs) — and protein degradation, which occurs through ubiquitin ligases such as SCF (SKP1–CUL1–F-box protein) complexes and APC/C (anaphase-promoting complex/cyclosome). Here, we explore the functionality and biology of the F-box proteins, SKP2 (S-phase kinase-associated protein 2) and β-TrCP (β-transducin repeat-containing protein), which are emerging as important players in cancer biogenesis owing to the deregulated proteolysis of their substrates.

摘要翻译： 

细胞周期中各时相的维持与保存是一个高度复杂且协调的过程。它通过磷酸化（由周期蛋白依赖性激酶（CDKs）介导）和蛋白质降解（由泛素连接酶如SCF（SKP1-CUL1-F-box蛋白）复合物和APC/C（后期促进复合体/环状体）介导）进行调控。在此，我们探讨F-box蛋白SKP2（S期激酶相关蛋白2）和β-TrCP（含β-转导素重复蛋白）的功能与生物学特性，由于它们底物的蛋白水解失调，它们正在成为癌症发生中的重要参与者。

原文链接：

Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer