title: A cellular response linking eIF4AI activity to eIF4AII transcription.
abstract: The recruitment of ribosomes to eukaryotic cellular mRNAs requires the activity of two prototypic RNA helicases, eukaryotic initiation factor (eIF) 4AI and eIF4AII. The eIF4A isoforms are highly conserved, are thought to be functionally interchangeable, and are directed to the 5' m(7)GpppN cap structure of mRNAs during translation initiation by virtue of their assembly into eIF4F, a heterotrimeric complex that also harbors the eIF4E cap binding protein and eIF4G scaffolding unit. During the course of RNA interference experiments aimed at investigating the respective roles of eIF4AI and eIF4AII in translation, we uncovered a cellular response pathway whereby suppression of eIF4AI increases transcription of the eIF4AII gene, leading to elevated eIF4AII mRNA and protein levels. Inhibition of eIF4AI suppresses protein synthesis, and although eIF4AII protein levels increase above and beyond what should be sufficient to compensate for the decrease in eIF4AI levels, there is no corresponding rescue of translation or of the block on cellular proliferation that occurs upon eIF4AI suppression. These results were phenocopied using the small molecule eIF4A inhibitor hippuristanol. Taken together, our results indicate that eIF4AI and eIF4AII expression appear linked and that the two protein isoforms exhibit functional differences.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Galicia-Vázquez
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.forename: Francis
authors.initials: F
authors.lastname: Robert
authors.forename: Aouod Quang
authors.initials: AQ
authors.lastname: Agenor
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013261:Sterols / Q000494:pharmacology; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D013261:Sterols; C510125:hippuristanol; D039601:Eukaryotic Initiation Factor-4A