title: Translational control by mTOR-independent routes: how eIF6 organizes metabolism.
abstract: Over the past few years, there has been a growing interest in the interconnection between translation and metabolism. Important oncogenic pathways, like those elicited by c-Myc transcription factor and mTOR kinase, couple the activation of the translational machinery with glycolysis and fatty acid synthesis. Eukaryotic initiation factor 6 (eIF6) is a factor necessary for 60S ribosome maturation. eIF6 acts also as a cytoplasmic translation initiation factor, downstream of growth factor stimulation. eIF6 is up-regulated in several tumor types. Data on mice models have demonstrated that eIF6 cytoplasmic activity is rate-limiting for Myc-induced lymphomagenesis. In spite of this, eIF6 is neither transcriptionally regulated by Myc, nor post-transcriptionally regulated by mTOR. eIF6 stimulates a glycolytic and fatty acid synthesis program necessary for tumor growth. eIF6 increases the translation of transcription factors necessary for lipogenesis, such as CEBP/β, ATF4 and CEBP/δ. Insulin stimulation leads to an increase in translation and fat synthesis blunted by eIF6 deficiency. Paradoxycally, long-term inhibition of eIF6 activity increases insulin sensitivity, suggesting that the translational activation observed upon insulin and growth factors stimulation acts as a feed-forward mechanism regulating lipid synthesis. The data on the role that eIF6 plays in cancer and in insulin sensitivity make it a tempting pharmacological target for cancers and metabolic diseases. We speculate that eIF6 inhibition will be particularly effective especially when mTOR sensitivity to rapamycin is abrogated by RAS mutations.
authors.affiliation: National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi' - INGM, via F. Sforza 35, Milano, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Miluzio
authors.affiliation: National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi' - INGM, via F. Sforza 35, Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ricciardi
authors.affiliation: National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi' - INGM, via F. Sforza 35, Milano, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Manfrini
authors.affiliation: National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi' - INGM, via F. Sforza 35, Milano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Alfieri
authors.affiliation: National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi' - INGM, via F. Sforza 35, Milano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Oliveto
authors.affiliation: Molecular Oncology Group, Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Via Mirasole 22A, Bellinzona, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brina
authors.affiliation: National Institute of Molecular Genetics 'Romeo ed Enrica Invernizzi' - INGM, via F. Sforza 35, Milano, Italy.|Department of Biosciences, University of Milan, Via Celoria 26, Milano 20133, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008659:Metabolic Diseases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D022782:CCAAT-Enhancer-Binding Protein-beta; D007004:Hypoglycemic Agents; D007328:Insulin; D010448:Peptide Initiation Factors; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C021019:eIF-6; D051701:Activating Transcription Factor 4; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Myc; fatty acid synthesis; glycolysis; mechanistic target of rapamycin; translation factors