title: Translational dysregulation in cancer: eIF4A isoforms and sequence determinants of eIF4A dependence.
abstract: The malignant phenotype is largely the consequence of dysregulated gene expression. Transformed cells depend upon not just a global increase in protein synthesis but an altered translational landscape in which pro-oncogenic mRNAs are translationally up-regulated. Such mRNAs have been shown to possess longer and more structured 5'-UTRs requiring high levels of eukaryotic initiation factor 4A (eIF4A) helicase activity for efficient translation. As such there is a developing focus on targeting eIF4A as a cancer therapy. In order for such treatments to be successful, we must develop a detailed understanding of the mechanisms which make specific mRNAs more dependent on eIF4A activity than others. It is also crucial to fully characterize the potentially distinct roles of eIF4A1 and eIF4A2, which until recently were thought to be functionally interchangeable. This review will highlight the recent advances made in this field that address these issues.
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, U.K.
authors.forename: Farheen
authors.initials: F
authors.lastname: Raza
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, U.K.
authors.forename: Joseph Alexander
authors.initials: JA
authors.lastname: Waldron
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, U.K. Department of Cancer Studies, University of Leicester, Leicester, LE1 9HN, U.K. jlq2@leicester.ac.uk.
authors.forename: John Le
authors.initials: JL
authors.lastname: Quesne
mesh_terms: D004852:Epoxy Compounds / Q000627:therapeutic use; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018942:Macrolides / Q000627:therapeutic use; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013261:Sterols / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use; D014315:Triterpenes / Q000627:therapeutic use; D001572:Benzofurans
chemical_list: D004852:Epoxy Compounds; D039601:Eukaryotic Initiation Factor-4A; D018942:Macrolides; D020033:Protein Isoforms; D013261:Sterols; D013844:Thiazoles; D014315:Triterpenes; C510125:hippuristanol; C421324:pateamine A; C489897:silvestrol; D001572:Benzofurans
keywords: 5′-untranslated region (5′-UTR); G-quadruplex; cancer; eukaryotic initiation factor 4A (eIF4A); mRNA helicase; translation