文章：

不断扩大的p53靶点范围

The expanding universe of p53 targets

原文发布日期：2009-10-01

DOI: 10.1038/nrc2730

类型: Review Article

开放获取: 否

要点：

1. p53 is a key tumour suppressor and master regulatory transcription factor that is altered in most human cancers. Several stresses lead to p53 activation, which results in various biological outcomes, including cell cycle arrest and apoptosis. Each of these events seems to contribute to tumour suppression. The p53 network can be affected by variation in p53 levels and the variety of genes targeted.
2. The extent of p53 transactivation and transcriptional repression is influenced by many factors, including p53 levels, cofactors and the specific response element (RE) sequences, all of which contribute to the role that p53 has in the aetiology of cancer. Cooperativity in cis between p53 and other transcription factors, such as oestrogen receptors, in the activation of canonical and non-canonical REs greatly expands the p53 master regulatory network.
3. Essential components in the p53-mediated transactivation of target genes are the p53 RE sequences, which differ individually from the consensus sequence and support p53 transactivation to varying extents. Transactivation assays developed in budding yeast and human cells have been valuable tools for defining and assessing the p53 transcriptional functionality of potential RE targets.
4. Non-canonical sequences that differ significantly from consensus can also support transactivation by p53, thereby greatly expanding the p53 transcriptional network. Canononical and non-canonical p53 REs can be transactivated by several p53 mutants with altered functionality, many of which are associated with cancer.
5. Using information about the functionality of p53 REs, it seems that in the evolution of humans and primates many DNA metabolism and repair genes have evolved to become responsive to p53 through the inclusion of functional p53 REs.

要点翻译：

1. p53是一种关键的肿瘤抑制因子和主调控转录因子，在大多数人类癌症中发生改变。多种应激信号会激活p53，进而引发包括细胞周期阻滞和凋亡在内的多种生物学效应。这些事件均对肿瘤抑制具有重要作用。p53网络可能受p53水平变化及其靶基因多样性的影响。
2. p53反式激活与转录抑制的程度受多种因素影响，包括p53水平、辅因子及特异性应答元件序列，这些因素共同参与了p53在癌症病因学中发挥作用的过程。在典型和非典型应答元件的激活过程中，p53与雌激素受体等其他转录因子在顺式作用上的协同效应，极大地扩展了p53主调控网络。
3. p53介导靶基因反式激活的核心组分是p53应答元件序列。这些序列与共有序列存在个体差异，并在不同程度上支持p53的反式激活功能。在芽殖酵母和人类细胞中开发的反式激活检测技术，已成为界定和评估潜在应答元件靶点p53转录功能的重要工具。
4. 与共有序列差异显著的非典型序列同样能够支持p53的反式激活，从而极大拓展了p53转录网络。典型和非典型p53应答元件均可被多种功能改变的p53突变体反式激活，其中许多突变体与癌症相关。
5. 通过分析p53应答元件的功能性特征可以发现，在人类和灵长类动物的进化过程中，许多DNA代谢与修复基因通过整合功能性p53应答元件，进化出了对p53的响应能力。

英文摘要：

The p53 tumour suppressor is modified through mutation or changes in expression in most cancers, leading to the altered regulation of hundreds of genes that are directly influenced by this sequence-specific transcription factor. Central to the p53 master regulatory network are the target response element (RE) sequences. The extent of p53 transactivation and transcriptional repression is influenced by many factors, including p53 levels, cofactors and the specific RE sequences, all of which contribute to the role that p53 has in the aetiology of cancer. This Review describes the identification and functionality of REs and highlights the inclusion of non-canonical REs that expand the universe of genes and regulation mechanisms in the p53 tumour suppressor network.

摘要翻译： 

p53肿瘤抑制因子在大多数癌症中通过突变或表达变化而被修饰，导致数百个直接受这一序列特异性转录因子影响的基因调控发生改变。p53主调控网络的核心是靶标应答元件（RE）序列。p53的转激活和转录抑制程度受多种因素影响，包括p53水平、辅因子以及特定的RE序列，所有这些因素共同决定了p53在癌症病因学中的作用。本综述描述了RE的鉴定与功能，并强调了非经典RE的加入，这些RE扩展了p53肿瘤抑制网络中的基因和调控机制的范围。

原文链接：

The expanding universe of p53 targets