title: eIF6 anti-association activity is required for ribosome biogenesis, translational control and tumor progression.
abstract: Here we discuss the function of eukaryotic initiation factor 6 (eIF6; Tif6 in yeast). eIF6 binds 60S ribosomal subunits and blocks their joining to 40S. In this context, we propose that eIF6 impedes unproductive 80S formation, namely, the formation of 80S subunits without mRNA. Genetic evidence shows that eIF6 has a dual function: in yeast and mammals, nucleolar eIF6 is necessary for the biogenesis of 60S subunits. In mammals, cytoplasmic eIF6 is required for insulin and growth factor-stimulated translation. In contrast to other translation factors, eIF6 activity is not under mTOR control. The physiological significance of eIF6 impacts on cancer and on inherited Shwachman-Bodian-Diamond syndrome. eIF6 is overexpressed in specific human tumors. In a murine model of lymphomagenesis, eIF6 depletion leads to a striking increase of survival, without adverse effects. Shwachman-Bodian-Diamond syndrome is caused by loss of function of SBDS protein. In yeast, point mutations of Tif6, the yeast homolog of eIF6, rescue the quasi-lethal effect due to the loss of the SBDS homolog, Sdo1. We propose that eIF6 is a node regulator of ribosomal function and predict that prioritizing its pharmacological targeting will be of benefit in cancer and Shwachman-Bodian-Diamond syndrome. This article is part of a Special Issue entitled: Translation and Cancer.
authors.affiliation: INGM, "Romeo ed Enrica Invernizzi," Milano 20122, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brina
authors.affiliation: INGM, "Romeo ed Enrica Invernizzi," Milano 20122, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Miluzio
authors.affiliation: INGM, "Romeo ed Enrica Invernizzi," Milano 20122, Italy; DISIT, Alessandria 15100, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ricciardi
authors.affiliation: INGM, "Romeo ed Enrica Invernizzi," Milano 20122, Italy; DISIT, Alessandria 15100, Italy. Electronic address: biffo@ingm.org.
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
mesh_terms: D000818:Animals; D001855:Bone Marrow Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008068:Lipomatosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D054683:Ribosome Subunits, Large, Eukaryotic / Q000235:genetics / Q000378:metabolism*; D000081003:Shwachman-Diamond Syndrome; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators
chemical_list: C109284:EIF6 protein, human; D039642:Eukaryotic Initiation Factors; D047908:Intracellular Signaling Peptides and Proteins; C115811:Itgb4bp protein, mouse; D009363:Neoplasm Proteins; D010448:Peptide Initiation Factors; C408468:SCAND1 protein, human; D015534:Trans-Activators; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: PKC; RACK1; eIF6