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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2017 (publ. 2016, arch)     Display Documents

ID: 732159.0, MPI für molekulare Biomedizin / Jahrbuch 2017 (publ. 2016, arch)
Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer
Authors:Delaunay, Sylvain; Rapino, Francesca; Tharun, Lars; Zhou, Zhaoli; Heukamp, Lukas; Termathe, Martin; Shostak, Kateryna; Klevernic, Iva; Florin, Alexandra; Desmecht, Hadrien; Desmet, Christophe J; Nguyen, Laurent; Leidel, Sebastian A; Willis, Anne E; Büttner, Reinhard; Chariot, Alain; Close, Pierre
Date of Publication (YYYY-MM-DD):2016-10-17
Title of Journal:The Journal of Experimental Medicine
Issue / Number:11
Start Page:2503
End Page:2523
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Posttranscriptional modifications of transfer RNAs (tRNAs) at the wobble uridine 34 (U34) base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcm5s2-tRNA modification, are up-regulated in human breast cancers and sustain metastasis. Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer. Mechanistically, ELP3 and CTU1/2 support cellular invasion through the translation of the oncoprotein DEK. As a result, DEK promotes the IRES-dependent translation of the proinvasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcm5s2-tRNA modification, escapes the ELP3- and CTU1-dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate that the key role of U34 tRNA modification is to support specific translation during breast cancer progression and highlight a functional link between tRNA modification– and IRES-dependent translation during tumor cell invasion and metastasis.
External Publication Status:published
Document Type:Article
Communicated by:Jeanine Müller-Keuker
Affiliations:MPI für molekulare Biomedizin
Identifiers:URL:http://www.jem.org/lookup/doi/10.1084/jem.20160397... [ID No:1]
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