Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation
Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation
复制标题
DOI：
10.1038/sj.onc.1209996
复制
发表时间：
2006-11-01
期刊：
影响因子：
8
通讯作者：
Fahraeus, R.
中科院分区：
文献类型：
--
作者：
Candeias, M. M.;Powell, D. J.;Fahraeus, R.
P53通过对多种细胞应激作出反应来控制细胞的生长和存活。然而，不同的p53激活途径如何导致细胞周期停滞或细胞凋亡，目前尚未完全了解。我们及其他研究人员已经描述了一种从p53信使核糖核酸（mRNA）的第二个翻译起始位点产生的N端截短的p53蛋白（p53/47），它可以与p53相互作用，并使p53复合物的稳定性和反式激活特性发生改变。在此我们表明，依赖帽结构和不依赖帽结构的起始机制调控着p53 mRNA的翻译。全长p53或p53/47合成的变化是通过作用于p53 mRNA不同区域的独特的细胞应激诱导途径来调控的。我们还表明，一些细胞毒性药物需要全长p53的存在才能诱导细胞凋亡，而对于其他药物，p53/47就足够了。这表明，由于具有可选择的翻译起始位点，p53 mRNA产生不同水平的p53异构体，这有助于协调p53在应对不同类型细胞应激时激活的细胞生物学结果。这为p53整合和区分细胞环境中大量变化的方式提供了新的视角。
P53 controls the growth and survival of cells by acting in response to a multitude of cellular stresses. It is, however, not yet fully understood how different p53 activation pathways result in either cell cycle arrest or apoptosis. We and others have described an N-terminally truncated p53 protein (p53/47) originating from a second translation initiation site in the p53 messenger RNA ( mRNA), which can interact with p53 and impose altered stability and transactivation properties to p53 complexes. Here we show that cap-dependent and cap-independent mechanisms of initiation govern the translation of the p53 mRNA. Changes in synthesis of full-length p53 or p53/47 are regulated through distinct cell stress-induced pathways acting through separate regions of the p53 mRNA. We also show that some cytotoxic drugs require the presence of full-length p53 to induce apoptosis, whereas for others p53/47 is sufficient. This indicates that by harbouring alternative translation initiation sites, the p53 mRNA gives rise to different levels of the p53 isoforms which help to orchestrate the cell biological outcome of p53 activation in response to different types of cell stress. This sheds new light into the way p53 can integrate and differentiate a large multiplicity of changes in the cellular environment.