Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth

Annarita Miluzio; Anne Beugnet; Stefano Grosso; Daniela Brina; Marilena Mancino; Stefano Campaner; Bruno Amati; Ario de Marco; Stefano Biffo

doi:10.1016/j.ccr.2011.04.018

Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth

Annarita Miluzio
, Anne Beugnet
, Stefano Grosso
, Daniela Brina
, Marilena Mancino
, Stefano Campaner
, Bruno Amati
, Ario de Marco
, Stefano Biffo

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	765-775
Number of pages	11
Journal	Cancer Cell
Volume	19
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2011.04.018
Publication status	Published - 14 Jun 2011
Externally published	Yes

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SDG 3 Good Health and Well-being

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10.1016/j.ccr.2011.04.018

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@article{928b0aa295784d92bf90aeaf28149775,

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.",

author = "Annarita Miluzio and Anne Beugnet and Stefano Grosso and Daniela Brina and Marilena Mancino and Stefano Campaner and Bruno Amati and \{de Marco\}, Ario and Stefano Biffo",

note = "Funding Information: We thank J.-W. Soh for GST-MARCKS, C. Proud for GST-4EBP1, D. Ruggero for HCV-IRES plasmid, V. Ruggeri for preliminary B cell purification, E. Pesce for help with kinase assays, E. Ranzato for assistance with 2D-gels, P. Capasso for recombinant eIF6 purification, C. Doglioni e M. Ponzoni for histological diagnosis, S. Bandiera for critical reading. We thank for helpful discussions and advice P. Della Bona, V. Volta, and C. Gorrini. Special thanks to P.C. Marchisio for generous intellectual and material support at the start of the project and to N. Offenhaeuser for critical suggestions. The authors are upported by grants from Associazione Italiana Ricerca sul Cancro, AIRC (S.B., B.A.), Association for International Cancer Research, AICR (S.B.), Italian Health Ministry (S.B., B.A.). S.G. is a recipient of a fellowship from Regione Piemonte. There are MTAs or patents restricting use of materials listed, described as: antibodies directed against eIF6; recombinant eIF6; mouse mutants for eIF6. ",

year = "2011",

month = jun,

day = "14",

doi = "10.1016/j.ccr.2011.04.018",

language = "English",

volume = "19",

pages = "765--775",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

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T1 - Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth

AU - Miluzio, Annarita

AU - Beugnet, Anne

AU - Grosso, Stefano

AU - Brina, Daniela

AU - Mancino, Marilena

AU - Campaner, Stefano

AU - Amati, Bruno

AU - de Marco, Ario

AU - Biffo, Stefano

N1 - Funding Information: We thank J.-W. Soh for GST-MARCKS, C. Proud for GST-4EBP1, D. Ruggero for HCV-IRES plasmid, V. Ruggeri for preliminary B cell purification, E. Pesce for help with kinase assays, E. Ranzato for assistance with 2D-gels, P. Capasso for recombinant eIF6 purification, C. Doglioni e M. Ponzoni for histological diagnosis, S. Bandiera for critical reading. We thank for helpful discussions and advice P. Della Bona, V. Volta, and C. Gorrini. Special thanks to P.C. Marchisio for generous intellectual and material support at the start of the project and to N. Offenhaeuser for critical suggestions. The authors are upported by grants from Associazione Italiana Ricerca sul Cancro, AIRC (S.B., B.A.), Association for International Cancer Research, AICR (S.B.), Italian Health Ministry (S.B., B.A.). S.G. is a recipient of a fellowship from Regione Piemonte. There are MTAs or patents restricting use of materials listed, described as: antibodies directed against eIF6; recombinant eIF6; mouse mutants for eIF6.

PY - 2011/6/14

Y1 - 2011/6/14

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/79958709853

U2 - 10.1016/j.ccr.2011.04.018

DO - 10.1016/j.ccr.2011.04.018

M3 - Article

SN - 1535-6108

VL - 19

SP - 765

EP - 775

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth

Abstract

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