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

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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.