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The role of poly(A) metabolism in growth factor induced gene expression

Poly(A) 代谢在生长因子诱导的基因表达中的作用

基本信息

批准号：
BB/K008021/1
负责人：
Cornelia Huiberdina De Moor
金额：
$ 69.45万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK008021%2F1
关键词：
role poly metabolism growth factor

项目摘要

A relatively small number of genes can react rapidly to changes in and around the cell and regulate other genes to coordinate an appropriate cellular response. These master control genes are very important for medicine as their misregulation is often involved in diseases such as cancer, asthma and stroke. In addition, a similar rapid change in the activity of genes is required for the production of proteins for medical and industrial applications. Because the master control genes also need to be able to turn off quickly, their products have to be degraded fast. However, this creates a problem, as it is hard to accumulate sufficient product if it degrades quickly (if someone is eating your pancakes as quickly you bake them, you never get any yourself). We have recently shown that a modification to the gene product allows a delay before degradation occurs, making it possible to both accumulate product and remove it quickly (if you agree that pancake eating only starts after everyone, including you, is at the table, a pile of pancakes can accumulate and then be removed even faster). In this project, we will measure this delay during the stimulation of cell growth with growth factor and determine if it indeed plays such a big role. We will investigate which genes use a delayed decay and what causes differences in the delay between genes. Interestingly, we found that a compound from the traditional medicinal mushroom Cordyceps, cordycepin, reduced the activity of many master control genes for inflammation and cell growth. It inhibits the process that causes delay in decay of their products, which may explain how the drug works. We therefore want to find out if cordycepin indeed works this way and if it is a good candidate for a novel class of cancer drugs (by inhibiting mostly growth factor activated genes) or if it has effects on too many other genes, which would lead to nasty side effects.Our findings will be important for the understanding of the regulation of master control genes and are therefore likely to benefit medical research and the industrial production of proteins. The work on cordycepin may ultimately lead to new medicines for cancer and inflammatory disease.

相对较少的基因可以对细胞内和细胞周围的变化做出快速反应，并调节其他基因以协调适当的细胞反应。这些主控基因对医学非常重要，因为它们的失调经常与癌症、哮喘和中风等疾病有关。此外，医疗和工业用蛋白质的生产也需要类似的基因活性快速变化。因为主控基因也需要能够快速关闭，它们的产物必须快速降解。然而，这产生了一个问题，因为如果它降解得很快，就很难积累足够的产品（如果有人吃你烤的煎饼和你烤的煎饼一样快，你自己永远不会得到任何东西）。我们最近的研究表明，对基因产物的修饰可以延缓降解的发生，从而使产物的积累和快速清除成为可能（如果你同意吃煎饼只有在包括你在内的每个人都在餐桌上之后才开始，那么一堆煎饼可以积累起来，然后更快地被清除）。在这个项目中，我们将测量生长因子刺激细胞生长过程中的这种延迟，并确定它是否确实起着如此大的作用。我们将研究哪些基因使用延迟衰减以及导致基因之间延迟差异的原因。有趣的是，我们发现一种来自传统药用蘑菇冬虫夏草的化合物，冬虫夏草素，降低了许多炎症和细胞生长的主要控制基因的活性。它抑制了导致其产物延迟衰变的过程，这可能解释了药物的作用原理。因此，我们想知道冬虫夏草素是否确实以这种方式起作用，它是否是一种新型抗癌药物的良好候选者（通过抑制大部分生长因子激活的基因），或者它是否对太多其他基因有影响，这将导致严重的副作用。我们的发现对于理解主控基因的调控非常重要，因此可能有益于医学研究和蛋白质的工业生产。虫草素的研究可能最终导致癌症和炎症疾病的新药。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-Wide Analysis of PAPS1-Dependent Polyadenylation Identifies Novel Roles for Functionally Specialized Poly(A) Polymerases in Arabidopsis thaliana.

PAPS1依赖性聚腺苷酸化的全基因组分析确定了拟南芥功能专业的聚（A）聚合酶的新作用。

DOI：
10.1371/journal.pgen.1005474
发表时间：
2015-08
期刊：
PLoS genetics
影响因子：
4.5
作者：
Kappel C;Trost G;Czesnick H;Ramming A;Kolbe B;Vi SL;Bispo C;Becker JD;de Moor C;Lenhard M
通讯作者：
Lenhard M

The role of acid-base imbalance in statin-induced myotoxicity.