文章：

离婚的ARF和p53：一个悬而未决的案件

Divorcing ARF and p53: an unsettled case

原文发布日期：2006-08-17

DOI: 10.1038/nrc1954

类型: Review Article

开放获取: 否

要点：

1. The ARF tumour suppressor interferes with the MDM2 E3 ubiquitin protein ligase to stabilize and activate the p53 transcription factor, triggering cell-cycle arrest or apoptosis.
2. It is widely accepted that the activity of ARF is mediated through the activation of the p53 transcription programme, but several lines of evidence, much of it controversial, indicate that ARF also exerts p53-independent tumour-suppressor functions.
3. The ARF protein has an unusual amino-acid composition, being highly basic (pI>12, despite a paucity of lysine residues); it is probably unstructured unless bound to other targets and highly promiscuous in its binding.
4. ARF is a nucleolar protein that assembles into high-molecular-mass complexes with nucleophosmin (NPM). Its binding to NPM inhibits ARF turnover and results in its accumulation within the nucleolus.
5. ARF has an associated sumoylating activity that can lead to the modification of proteins to which it binds, including MDM2 and NPM.
6. ARF has now been reported to physically interact with more than 25 other proteins, at least some of which have been postulated to be responsible for its p53-independent functions. These include proteins involved in ribosome biogenesis, transcriptional regulation, the DNA-damage response, apoptosis and autophagy. How strong are the data?

要点翻译：

1. ARF肿瘤抑制蛋白通过干扰MDM2 E3泛素蛋白连接酶来稳定并激活p53转录因子，从而引发细胞周期停滞或凋亡。
2. 学界普遍认为ARF的活性是通过激活p53转录程序介导的，但多项证据（其中存在较多争议）表明ARF还具有不依赖于p53的肿瘤抑制功能。
3. ARF蛋白具有独特的氨基酸组成，其碱性极强（等电点>12，尽管缺乏赖氨酸残基）；除非与其他靶标结合，该蛋白可能呈非结构化状态，且具有高度混杂的结合特性。
4. ARF是一种核仁蛋白，可与核磷蛋白（NPM）组装成高分子复合物。其与NPM的结合能抑制ARF的周转，导致其在核仁内积聚。
5. ARF具有相关的类泛素化活性，可修饰其结合蛋白（包括MDM2和NPM）。
6. 目前研究发现ARF能与超过25种其他蛋白质发生物理相互作用，其中至少部分被推测与其p53非依赖性功能相关。这些蛋白涉及核糖体生物合成、转录调控、DNA损伤应答、凋亡及自噬过程。现有证据的说服力如何？

英文摘要：

Mammalian cells that sustain oncogenic insults can invoke defensive programmes that either halt their division or trigger their apoptosis, but these countermeasures must be finely tuned to discriminate between physiological and potentially harmful growth-promoting states. By functioning specifically to oppose abnormally prolonged and sustained proliferative signals produced by activated oncogenes, the ARF tumour suppressor antagonizes functions of MDM2 to induce protective responses that depend on the p53 transcription factor and its many target genes. However, ARF has been reported to physically associate with proteins other than MDM2 and to have p53-independent activities, most of which remain controversial and poorly understood.

摘要翻译： 

当哺乳动物细胞遭受致癌损伤时，可启动防御程序，使其停止分裂或触发凋亡；但这些防御必须精准校准，以区分生理性增殖与潜在有害的促生长状态。ARF抑癌蛋白通过特异性对抗由活化癌基因产生的异常持久增殖信号，拮抗MDM2的功能，从而依赖p53转录因子及其众多靶基因诱导保护性反应。然而，据报道ARF还能与MDM2以外的蛋白物理结合，并具有不依赖p53的活性，其中多数仍存在争议且机制不清。

原文链接：

Divorcing ARF and p53: an unsettled case