Sketch of a
tandem zinc finger domain in contact with a class II AU-rich element (PDB:
1RGO). Sidechains involved in stacking interatcions with nucleic acids
(red) are shown in blue.Abstract
Regulation of gene expression by changes in mRNA stability is one of the most important control mechanisms of gene expression in the immune system. The decay rate of mRNA is regulated by cis-acting elements in the 3' untranslated regions of mRNA. The most prominent regulatory elements are the so called AU-rich elements (AREs). AREs recruit various ARE-binding proteins that possess RNA stabilizing or destabilizing functions. One of the key mRNA-destabilizing proteins is tristetraprolin (TTP). TTP deficiency leads to serious inflammation and eventually death in animal models caused most likely by insufficient removal of proinflammatory mRNAs such as TNFα. The biological function of TTP is still not completely understood due to the lack of animal models with conditional regulation of TTP expression. Since the function of TTP is entirely linked to the target mRNAs it will be essential to identify new TTP targets that are still underexplored. In the proposed multidisciplinary project, TTP targets will be identified by a number of large scale experimental methods. The sequence of these mRNAs will be investigated for the presence of common sequence and structural elements using bioinformatics. Based on these data, prediction tools for TTP targets will be developed and integrated in a searchable TTP target database that will be publically accessible via the internet. In addition, using the prediction tools modifiers (small RNA molecules) of the TTP binding will be designed and subsequently experimentally tested for their potential to modulate TTP function
in vivo. Altogether, the proposed project uses experimental methods in combination with bioinformatics tools to establish a broad range relationship linking mRNA structure/sequence with TTP targets and TTP function.
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