The overall rate of protein synthesis is an important factor modulating cell and tissue metabolism. In addition, the translational machinery plays key roles in controlling gene-specific expression in eukaryotic cells. The regulatory mechanisms involve changes in the activities of components of translational complexes that lead to selective translation of specific subsets of messenger RNAs. Modulations of translational activity are primarily mediated by changes in the phosphorylation states of translation factors or RNA-binding proteins promoting specific modes of translation. Kinases closely associated with translation initiation complexes have a huge potential to regulate selective modes of translation. However, despite many studies on signalling pathways controlling the phosphorylation status of the translation machinery, little is known about how these modifications regulate the quality of the translation. The main research objective is to uncover novel molecular mechanisms regulating the expression of specific genes at the translation level triggered by signalling pathways. The project proposed will make use of a variety of modern molecular biology, biochemistry and cell biology techniques, including detailed proteomic and genomic analyses. In addition, the clinical relevance of the new identified mechanism will be analysed in human brain cancer. Understanding the mechanisms selecting specific mRNAs for translation would not only explain the principles underlying rapid signalling responses controlling translation and the phenotypical consequences but would also allow development of molecular strategies for therapeutic interference in human diseases with deregulated signalling pathways.
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