Increasing Eukaryotic Initiation Factor 6 (eIF6) Gene Dosage Stimulates Global Translation and Induces a Transcriptional and Metabolic Rewiring that Blocks Programmed Cell Death [article]

Arianna Russo, Guido Gatti, Roberta Alfieri, Elisa Pesce, Kelly Soanes, Sara Ricciardi, Cristina Cheroni, Thomas Vaccari, Stefano Biffo, Piera Calamita
2017 bioRxiv   pre-print
Increases in ribosomal proteins and initiation factors are often observed in tumours and required during development. Haploinsufficient models have shown that such elevation is essential for tumour growth. Models with increased gene dosage of initiation factors, addressing the effects of their forced overexpression are lacking. The eukaryotic Initiation Factor 6 (eIF6) gene is amplified in some cancers and overexpressed in most, while it has been demonstrated that eIF6 haploinsufficiency
more » ... s mice from lymphomagenesis. eIF6 is necessary for ribosome biogenesis and efficient translation, and is present as a single gene in all animal species. Taking advantage of genetic tractability of Drosophila melanogaster, we generated an in vivo model of eIF6 upregulation, in order to assess the early effects of increased gene dosage of this initiation factor. eIF6 overexpression increases the general rate of translation, both in vivo and in vitro. Organ specific overexpression in the eye causes a rough phenotype. The increase of translation driven by eIF6 is accompanied by a complex transcriptional rewiring and a modulation of histone acetylation activity. Gene expression changes caused by eIF6 include a dominant upregulation of ribosome biogenesis, a shift in Programmed Cell Death (PCD) and inhibition of ecdysteroids biosynthesis. Administration of 20-HydroxyEcdysone or expression of p35 apoptotic modulator reverts some of the effects driven by high eIF6 levels. We conclude that the increased translation driven by high levels of eIF6 generates a transcriptional and hormonal rewiring that evidences the capability of the translational machinery to regulate specific gene expression and metabolism. In addition, our in vivo model could be useful to screen potential drugs to treat cells with altered eIF6 gene dosage.
doi:10.1101/201558 fatcat:csl4hcytdnekfilbe52rfxzagu