The Spriggs Lab
Dr Keith Spriggs, Dr Andrew Bottley, Mr Thomas Webb
Research - The Roles of eIF4A in the Translational Control of Gene Regulation
Translation initiation represents a major target for direct, rapid control of the rate of translation of genes involved in the regulation of many cellular processes. The most abundant translation initiation factor in the eukaryotic cell is the RNA helicase eIF4A. eIF4A is central to eukaryotic protein synthesis, its main function being to unwind mRNA structure that might otherwise be inhibitory to translation. It is required for maximal rates of protein synthesis from "difficult" mRNAs. Of the mRNAs so far identified that have been shown to require eIF4A for proper expression those whose protein products are involved in cell growth and differentiation predominate. There already exist natural product inhibitors of eIF4A and we have shown recently that treatment of HeLa cells with one such inhibitor (hippuristanol which acts to inhibit the RNA binding and RNA helicase activities of eIF4A) leads to rapid reduction in translation rates although a significant proportion of mRNAs are resistant to this inhibition. In contrast, Pateamine another small molecule inhibitor of eIF4A dependent translation, acts to increase eIF4A helicase activity, but prevents eIF4A recycling. In addition we have developed RNA aptamers which inhibit eIF4A function in vitro. All these data support a model in which eIF4A is required for efficient translation by a subset of mRNAs that contain structured 5' UTRs, particularly those that have a role in cancer.
Our group is investigating in the roles of eIF4A in regulating gene expression, particularly with respect to control of oncogenesis. In collaboration with Dr Stephanie Allen, we are using AFM and optical tweezers to investigate the single molecule behaviour of eIF4A.
We are also dissecting the roles of eIF4A by targeting specific aspects of its function, and using translational profiling to identify changes in the translation of individual mRNAs.
We are interested in the prospect of developing anti-cancer drugs that inhibit eIF4A function, and to this end we are developing assay systems which can be used in high-throughput searches for potential therapeutic agents
Dr Keith Spriggs (Lecturer in Gene Regulation)
Dr Andrew Bottley (Research Fellow)
Mr Thomas Webb (PhD student)