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

多肽的合成是mRNA翻译过程的结果，多肽最终在细胞中折叠并经过各种修饰以产生功能性蛋白质。因此，蛋白质合成是细胞中遗传物质DNA中的信息通过中间底物mRNA转化为蛋白质的过程。翻译控制允许蛋白质合成的快速变化，从而使细胞和生物体维持细胞稳态并对各种刺激（包括温度等环境扰动）做出反应。令人惊讶的是，在亚生理温度下（冷休克，<37℃）和恢复后，哺乳动物细胞中mRNA翻译和随后蛋白质合成的控制很少被描述，尽管冷休克被用于移植医学、心脏和脑部手术，涉及哺乳动物的冬眠、大脑可塑性和衰老，并在生物技术领域被用作改善重组蛋白生产的方法。此外，两种哺乳动物冷休克蛋白，冷诱导RNA结合蛋白（CIRP）和RNA结合基序蛋白3 （Rbm3）与翻译控制和各种癌症有关。据我们所知，我们是英国唯一一个研究哺乳动物细胞在冷休克时的翻译控制的小组。在早期的研究中，我们获得的数据表明，在27-32℃的低温下，哺乳动物细胞中的mRNA翻译和蛋白质合成受到冷特异性机制的控制。我们打算通过维持和扩大我们两个国际知名团队之间的联系来进一步我们的早期研究，利用相关方法的组合来研究我们的总体假设，即“在哺乳动物细胞冷休克时，一个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饰，核糖体40S蛋白亚基转换，合成含有特定反式作用因子识别的特征的mRNA，以及合成与翻译装置相互作用以帮助mRNA翻译的特定蛋白质。这些研究将进一步确定哺乳动物细胞冷休克时翻译的控制，显著提高我们对这种条件下蛋白质合成的理解，可能导致新的方法来改善哺乳动物细胞的蛋白质生产和治疗心脏和脑损伤。

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.