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

数量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，因为它们的错误调控经常与癌症、哮喘和中风等疾病有关。此外，用于医疗和工业应用的蛋白质的生产也需要基因活性的类似快速变化。因为主控基因也需要能够快速关闭，所以他们的产品必须快速降解。然而，这会带来一个问题，因为如果产品迅速降解，就很难积累足够的产品(如果有人像你烤煎饼一样快地吃了你的煎饼，你自己就永远得不到)。我们最近已经证明，对基因产物的修饰可以在降解发生之前延迟一段时间，从而既可以积累产品，又可以快速移除它(如果你同意只有在包括你在内的所有人都坐在餐桌前才开始吃煎饼的观点，那么一堆煎饼可能会积累起来，然后更快地被移除)。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，并确定它是否真的发挥了如此大的作用。我们将调查哪些基因使用延迟衰变，以及是什么导致了基因之间延迟的差异。有趣的是，我们发现传统药用蘑菇虫草中的一种化合物虫草素降低了许多控制炎症和细胞生长的主控基因的活性。它抑制了导致其产品延迟腐烂的过程，这可能解释了该药物的作用机理。因此，我们想知道虫草素是否真的是这样起作用的，它是否是一种新型抗癌药物的好候选者(通过抑制大多数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。我们的发现将对理解主控基因的调控非常重要，因此可能有助于医学研究和蛋白质的工业生产。对虫草素的研究可能最终会带来治疗癌症和炎症性疾病的新药。

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.