Post-transcriptional control of cellular stress responses

所有生物都暴露在各种环境压力下，对它们的生存构成挑战。压力可能包括热、冷、污染物、辐射、氧自由基和香烟烟雾中的化学物质等等。这些药物可以引起各种细胞应激反应，帮助细胞处理细胞生理学的变化。在最著名的应激途径是p53肿瘤抑制途径。p53蛋白是一种转录因子，在许多应激反应中被激活，包括上面列出的大多数应激反应。一般来说，转录因子帮助控制基因在任何给定时间的开启或关闭。激活的p53控制着几个基因，这些基因编码的蛋白质与一种叫做凋亡的细胞死亡有关，这种细胞死亡有助于消除高度受损的细胞。然而，对细胞压力的过度反应可能会杀死健康的细胞，损害健康的组织。事实上，众所周知，在小鼠模型中，过度活跃的p53会加速衰老。因此，在p53转录因子完成工作后关闭它和打开它一样重要。

All organisms are exposed to a variety of environmental stresses that pose a challenge to their survival. Stresses could include heat, cold, pollutants, radiation, oxygen radicals and chemicals in cigarette smoke, to name a few. These agents can elicit a variety of cellular stress responses that help cells deal with changes in cell physiology. Among the more renowned stress pathways is the p53 tumour suppressor pathway. The p53 protein is a transcription factor that is activated in response to many stresses, including most of those listed above. In general, transcription factors help control what genes are turned on or off at any given time. Activated p53 controls several genes that encode proteins involved in a form of cell death called apoptosis that helps eliminate highly damaged cells. However, over-reacting to cellular stresses could be detrimental by killing healthy cells, damaging healthy tissue. In fact, it is known that hyperactive versions of p53 accelerate aging in mouse models. Therefore, turning off the p53 transcription factor when its job is done is just as important as being able to turn it on. In recent years, my research program has been focussed on how the p53 response is shut off and controlled after a defined stress. We have found that the p53 response is designed to be able to turn on and off rapidly and that this involves the regulation of messenger RNAs (mRNAs) after they are made and is thus referred to as post-transcriptional regulation of gene expression. There are a variety of post-transcriptional regulatory steps that control the fate of mRNAs, including pre-mRNA splicing, alternative polyadenylation and microRNA-mediated gene silencing that all form a part of this proposal. In addition, we recently uncovered evidence that another well-known stress response is activated by a natural chemical from Ginkgo biloba leaves that interferes with the process of pre-mRNA splicing. Our work suggests that this stress pathway (the unfolded protein response) is initiated by the production of aberrant proteins and ultimately leads to the activation of three different transcription factors (XBP1, ATF3 and ATF6). We are proposing to decipher the link between pre-mRNA splicing defects and the unfolded protein response. In the present proposal, we will use a variety of technologies at the forefront of our field, including next generation sequencing, heterologous reporter constructs and CRISPR-mediated gene editing to address fundamental questions in gene regulation using the p53 response and the unfolded protein response to better understand the roles of post-transcriptional regulatory processes in maintaining homeostasis.