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Determining how the translation initiation complex drives oncogenic gene programmes in tumours


Cell Biology of Cancer

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Prof M Bushell , Prof J LeQuesne No more applications being accepted Funded PhD Project (Students Worldwide)

About the Project

The Cancer Research UK Beatson Institute is one of Europe's leading cancer research centres, supporting cutting-edge work into the molecular mechanisms of cancer development. We provide an outstanding research environment, underpinned by state-of-the-art core services and advanced technologies with special emphasis on imaging, metabolomics and in vivo models.

The mRNA translation apparatus, specifically the eIF4F complex, lies downstream of multiple mitogenic pathways, and integrates their signals to drive both global and specific protein synthesis. The core eIF4F complex consists of the cap-binding protein eIF4E, the regulatory scaffold eIF4G, and the ATP-dependent RNA helicase eIF4A. A number of auxiliary activating partners including eIF4B and eIF4H stimulate eIF4A and have oncogenic activity, while PDCD4 and 4E-binding proteins (4E-BPs) are inhibitory and are tumour suppressors. eIF4A plays a central role by unwinding secondary structure in 5’untranslated regions (5’UTRs) of mRNAs. This allows ribosome recruitment and subsequent scanning through the unwound 5’UTR until identification of the start codon and initiation of peptide synthesis. Therefore, it has been proposed that the amount of functional protein produced by a given mRNA is related both to the degree of structure within the 5’UTR and the level of eIF4A helicase activity. Crucially, oncogenic mRNAs, including c-myc and cyclins, are typified by highly structured GC-rich 5’UTRs. eIF4A knockdown or inhibition using small molecules both result in potent gene-specific translational downregulation of oncogene-encoding mRNAs with accompanying antiproliferative and antitumour effects in cell culture and animal models.

Our laboratories have amassed a huge quantity of data on how this complex drives oncogenic gene expression using a variety of advanced next-generation RNA sequencing techniques. These include ribosome profiling, which determines the exact codon position of elongating ribosomes; RIP-Seq, which identifies the mRNAs bound by these factors; iCLIP, which determines the exact interaction sites of a protein with an mRNA; and Structure-seq, which determines the secondary structure of all cellular mRNAs. This together with our in vitro reconstitution kinetic approaches allows us to directly probe hypotheses emerging from RNA sequencing methodologies and combining these techniques with mouse cancer models. Integration of this data is ongoing; however, it has become clear that the RNA is directing eIF4F complex activity and is not a passive substrate. Importantly, localised RNA motifs appear to stimulate the helicase activity of eIF4A, leading to the remodelling of localised RNA structure and allowing activation of translation.

This studentship will continue these investigations using advanced next-generation sequencing approaches combined with bioinformatics analysis. Hypotheses arising from these data will be tested using in vitro reconstitution experiments, cell culture and other model systems at the Beatson Institute, with the ultimate goal of defining how oncogenic gene expression is delivered in the tumour microenvironment. Importantly, our laboratories work closely with large pharmaceutical companies, developing novel therapeutics in this area, and the student will have the opportunity to interface with this consortium. In addition to the array of experimental approaches undertaken, direct investigation of how translation is dysregulated in human tumours will also be possible, and hypotheses will be tested in large cohorts of human patient material.

For informal enquiries, please contact Prof. Martin Bushell ([Email Address Removed]) or Prof. John LeQuesne ([Email Address Removed])

To apply, and for further details on the application process, please visit our website: http://www.beatson.gla.ac.uk/education/phd-students.htmlPlease do not email your CV.


Funding Notes

Studentships are funded for 4 years. The annual stipend will be £19,000.

References

RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.
Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, Mavrakis KJ, Jiang M, Roderick JE, Van der Meulen J, Schatz JH, Rodrigo CM, Zhao C, Rondou P, de Stanchina E, Teruya-Feldstein J, Kelliher MA, Speleman F, Porco JA Jr, Pelletier J, Rätsch G, Wendel HG.
Nature. 2014, 513(7516):65-70. doi: 10.1038/nature13485. Epub 2014 Jul 27.
MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression.
Knight JRP, Alexandrou C, Skalka GL, Vlahov N, Pennel K, Officer L, Teodosio A, Kanellos G, Gay DM, May-Wilson S, Smith EM, Najumudeen AK, Gilroy K, Ridgway RA, Flanagan DJ, Smith RCL, McDonald L, MacKay C, Cheasty A, McArthur K, Stanway E, Leach JDG, Jackstadt R, Waldron JA, Campbell AD, Vlachogiannis G, Valeri N, Haigis KM, Sonenberg N, Proud CG, Jones NP, Swarbrick ME, McKinnon HJ, Faller WJ, Le Quesne J, Edwards J, Willis AE, Bushell M, Sansom OJ.
Cancer Discov. 2020 CD-20-0652. doi: 10.1158/2159-8290.
mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity.
Waldron JA, Tack DC, Ritchey LE, Gillen SL, Wilczynska A, Turro E, Bevilacqua PC, Assmann SM, Bushell M, Le Quesne J.
Genome Biol. 2019 20(1):300. doi: 10.1186/s13059-019-1901-2.
eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR.
Wilczynska A, Gillen SL, Schmidt T, Meijer HA, Jukes-Jones R, Langlais C, Kopra K, Lu WT, Godfrey JD, Hawley BR, Hodge K, Zanivan S, Cain K, Le Quesne J, Bushell M.
Genome Biol. 2019 20(1):262. doi: 10.1186/s13059-019-1857-2.
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