Defining novel mechanisms of mRNA translational control upon cold-shock in mammalian cells

多肽的合成最终被折叠，并在细胞中进行各种修饰，以产生功能蛋白，这是一个称为信使核糖核酸翻译的过程。因此，蛋白质合成是一个过程，通过这个过程，细胞中遗传物质中的信息，DNA，通过中间底物mRNA转化为蛋白质。翻译控制允许蛋白质合成的快速变化，使细胞和有机体保持细胞内稳态，并对包括温度等环境扰动在内的各种刺激做出反应。令人惊讶的是，在亚生理温度(冷休克，37℃)和恢复时，对哺乳动物细胞中mRNA翻译和随后的蛋白质合成的控制描述得很少，尽管冷休克被用于移植医学、心脏和脑手术，与哺乳动物的冬眠、大脑可塑性和衰老有关，并被生物技术部门用作提高重组蛋白质生产的方法。此外，哺乳动物的两种冷休克蛋白，冷诱导RNA结合蛋白(CIRP)和RNA结合基序蛋白3(RBM3)与翻译控制和多种癌症有关。据我们所知，我们是英国唯一一个研究冷休克时哺乳动物细胞翻译控制的小组。在早期的研究中，我们产生的数据表明，在27-32摄氏度的冷休克中，特定的冷机制控制着哺乳动物细胞的mRNA翻译和蛋白质合成。我们打算通过保持和扩大我们两个国际知名组织之间的联系来进一步发展我们早期的研究，利用相互关联的方法来研究我们的总体假设，即‘在哺乳动物细胞中，冷休克时，涉及不同信号通路的协调反应被激活，导致翻译装置及其相互作用的修改，核糖体40S蛋白亚基的周转，包含特定反式作用因子识别特征的mRNAs的合成，以及与翻译装置相互作用的特定蛋白质的合成，以帮助mRNA翻译’。这些研究将进一步确定冷休克时哺乳动物细胞翻译的控制，显著提高我们对冷休克条件下蛋白质合成的理解，可能导致新的方法来提高哺乳动物细胞的蛋白质产量，并治疗心脏和脑损伤。

The synthesis of polypeptides that are ultimately folded and decorated with various modifications in the cell to yield a functional protein is the result of a process called mRNA translation. Protein synthesis is therefore the process by which the information in the genetic material in the cell, DNA is converted via an intermediary substrate mRNA, into proteins. Translational control allows for rapid changes in protein synthesis that permits cells and organisms to maintain cellular homeostasis and respond to various stimuli, including environmental perturbations such as temperature. Surprisingly, the control of mRNA translation and subsequent protein synthesis in mammalian cells at subphysiological temperatures (cold-shock, <37degC) and upon recovery is poorly described even though cold-shock is used in transplant medicine, heart and brain surgery, implicated in mammalian hibernation, brain plasticity and ageing, and is utilised in the biotechnology sector as a method to improve recombinant protein production. Further, the two mammalian cold-shock proteins, cold inducible RNA binding protein (CIRP) and RNA binding motif protein 3 (Rbm3) are implicated in translational control and various cancers. To our knowledge we are the only group in the UK investigating translational control in mammalian cells upon cold-shock. In earlier studies we have generated data that suggests cold specific mechanisms control mRNA translation and protein synthesis in mammalian cells upon cold-shock at 27-32degC. We intend to further our earlier studies by maintaining and extending the link between our two internationally known groups to utilise a combination of interrelated approaches to investigate our over-arching hypothesis that 'upon cold-shock in mammalian cells a coordinated response involving distinct signalling pathways is activated that results in modification of the translational apparatus and its interactions, ribosomal 40S protein subunit turnover, synthesis of mRNAs which contain features recognised by specific trans acting factors, and the synthesis of specific proteins that interact with the translational apparatus to aid mRNA translation'. These studies will further define the control of translation upon cold-shock in mammalian cells, significantly improving our understanding of protein synthesis under such conditions, potentially leading to new approaches to improve protein production from mammalian cells and treatments for heart and brain damage.