title: Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth.
abstract: Eukaryotic Initiation Factor 6 (eIF6) controls translation by regulating 80S subunit formation. eIF6 is overexpressed in tumors. Here, we demonstrate that eIF6 inactivation delays tumorigenesis and reduces tumor growth in vivo. eIF6(+/-) mice resist to Myc-induced lymphomagenesis and have prolonged tumor-free survival and reduced tumor growth. eIF6(+/-) mice are also protected by p53 loss. Myc-driven lymphomas contain PKCβII and phosphorylated eIF6; eIF6 is phosphorylated by tumor-derived PKCβII, but not by the eIF4F activator mTORC1. Mutation of PKCβII phosphosite of eIF6 reduces tumor growth. Thus, eIF6 is a rate-limiting controller of initiation of translation, able to affect tumorigenesis and tumor growth. Modulation of eIF6 activity, independent from eIF4F complex, may lead to a therapeutical avenue in tumor therapy.
authors.affiliation: Histology and Cell Growth, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Miluzio
authors.forename: Anne
authors.initials: A
authors.lastname: Beugnet
authors.forename: Stefano
authors.initials: S
authors.lastname: Grosso
authors.forename: Daniela
authors.initials: D
authors.lastname: Brina
authors.forename: Marilena
authors.initials: M
authors.lastname: Mancino
authors.forename: Stefano
authors.initials: S
authors.lastname: Campaner
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
authors.forename: Ario
authors.initials: A
authors.lastname: de Marco
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D016259:Genes, myc; D008223:Lymphoma / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010448:Peptide Initiation Factors / Q000502:physiology*; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000502:physiology; D064546:Protein Kinase C beta; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C115811:Itgb4bp protein, mouse; D010448:Peptide Initiation Factors; D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C; D064546:Protein Kinase C beta