文章：

p53抑制肿瘤：DNA损伤反应的作用？

Tumour suppression by p53: a role for the DNA damage response?

原文发布日期：2009-09-04

DOI: 10.1038/nrc2716

类型: Review Article

开放获取: 否

要点：

1. The p53 pathway mediates innate tumour suppression in cells that have sustained genetic changes that drive tumour initiation and progression. p53 functions principally as a transcription factor that alters gene expression in favour of biological events, such as senescence or apoptosis, and the outcome of these events blocks the proliferation of or eliminates the tumour cell.
2. Early-stage human tumours show evidence of DNA damage, suggesting that this could be the signal by which p53 recognizes the incipient tumour. This notion is supported by the finding that oncogenes can induce DNA damage in cultured cells.
3. By contrast, some animal models show that induction of p53 in response to DNA damage has little protective effect against tumour formation. The induction of p53 by the ARF tumour suppressor pathway in these animals seems to be crucial for mediating p53-dependent tumour suppression.
4. p53 knock-in mice lacking key p53 phosphorylation sites that are modified through the DNA damage pathways but not through the ARF pathway show increased tumour susceptibility, but in a limited number of tissues. These mice provide evidence to support the idea that DNA damage pathways can, at least partially, influence tumour suppressor function.

要点翻译：

1. p53通路在携带驱动肿瘤发生与进展的遗传改变的细胞中介导先天性肿瘤抑制。p53主要作为转录因子发挥作用，通过改变基因表达以促进衰老或凋亡等生物学过程，而这些过程的结果是阻断或清除肿瘤细胞的增殖。
2. 早期人类肿瘤显示出DNA损伤的证据，表明这可能是p53识别早期肿瘤的信号。这一观点得到以下发现的支持：癌基因能在培养细胞中诱导DNA损伤。
3. 相比之下，一些动物模型表明，DNA损伤诱导的p53激活对肿瘤形成的保护作用甚微。在这些动物中，ARF肿瘤抑制通路对p53的诱导似乎对介导p53依赖性肿瘤抑制至关重要。
4. 缺乏DNA损伤通路关键磷酸化位点（但保留ARF通路完整性）的p53基因敲入小鼠表现出肿瘤易感性增加，但仅限于少数组织。这些小鼠为以下观点提供了证据：DNA损伤通路至少能部分影响肿瘤抑制功能。

英文摘要：

Loss of p53 function occurs during the development of most, if not all, tumour types. This paves the way for genomic instability, tumour-associated changes in metabolism, insensitivity to apoptotic signals, invasiveness and motility. However, the nature of the causal link between early tumorigenic events and the induction of the p53-mediated checkpoints that constitute a barrier to tumour progression remains uncertain. This Review considers the role of the DNA damage response, which is activated during the early stages of tumour development, in mobilizing the tumour suppression function of p53. The relationship between these events and oncogene-induced p53 activation through the ARF pathway is also discussed.

摘要翻译： 

在几乎所有肿瘤类型的发生过程中，p53功能都会丧失。这为基因组不稳定性、肿瘤相关的代谢变化、对凋亡信号的不敏感、侵袭性和运动性铺平了道路。然而，早期致瘤事件与构成肿瘤进展屏障的p53介导检查点激活之间的因果关系性质仍不确定。本综述探讨了在肿瘤发展早期阶段被激活的DNA损伤反应，其在动员p53肿瘤抑制功能中的作用。还讨论了这些事件与通过ARF通路激活癌基因诱导的p53之间的关系。

原文链接：

Tumour suppression by p53: a role for the DNA damage response?