Article (Scientific journals)
Translational offsetting as a mode of estrogen receptor α-dependent regulation of gene expression
Lorent, J.; Kusnadi, E. P.; van Hoef, V. et al.
2019In EMBO Journal
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Keywords :
U34 tRNA modification; mRNA translation; Estrogen receptor
Abstract :
[en] Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNAs and corresponding protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome association, are reduced following ERα depletion lack features which limit translation efficiency including structured 5′UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modifying enzymes and thereby controls levels of U34-modified tRNAs. These findings unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs that may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers. © 2019 The Authors
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lorent, J.;  Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Kusnadi, E. P.;  Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
van Hoef, V.;  Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Rebello, R. J.;  Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
Leibovitch, M.;  Gerald Bronfman Department of Oncology and Departments of Biochemistry and Experimental Medicine, Lady Davis Institute, McGill University, Montreal, QC, Canada
Ristau, J.;  Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Chen, S.;  Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Lawrence, M. G.;  Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
Szkop, K. J.;  Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Samreen, B.;  Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Balanathan, P.;  Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
Rapino, Francesca  ;  Université de Liège - ULiège > Stem Cells-Cancer Signaling
Close, Pierre  ;  Université de Liège - ULiège > Stem Cells-Cancer Signaling
Bukczynska, P.;  Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Scharmann, K.;  Max Planck Institute for Molecular Biomedicine, Münster, Germany, Cells-in-Motion Cluster of Excellence, University of Münster, Münster, Germany
Takizawa, I.;  Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
Risbridger, G. P.;  Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
Selth, L. A.;  Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
Leidel, S. A.;  Max Planck Institute for Molecular Biomedicine, Münster, Germany, Cells-in-Motion Cluster of Excellence, University of Münster, Münster, Germany, Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland
Lin, Q.;  RNA Epitranscriptomics & Proteomics Resource, Department of Chemistry, University at Albany, Albany, NY, United States
Topisirovic, I.;  Gerald Bronfman Department of Oncology and Departments of Biochemistry and Experimental Medicine, Lady Davis Institute, McGill University, Montreal, QC, Canada
Larsson, O.;  Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Furic, L.;  Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
More authors (13 more) Less
Language :
English
Title :
Translational offsetting as a mode of estrogen receptor α-dependent regulation of gene expression
Publication date :
2019
Journal title :
EMBO Journal
ISSN :
0261-4189
eISSN :
1460-2075
Publisher :
Wiley-VCH Verlag
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Sverige Vetenskapsrådet
FRQS - Fonds de Recherche du Québec - Santé
CIHR - Canadian Institutes of Health Research
NHMRC - National Health and Medical Research Council
Swedish Foundation for International Cooperation in Research and Higher Education
U.S. Department of Health and Human Services
NIH - National Institutes of Health
Victorian Cancer Agency
Funding text :
Cancerföreningen i StockholmVetenskapsrådet, VRFonds de Recherche du Québec - Santé, FRQS: 34872Canadian Institutes of Health Research, CIHR: MOP‐363027National Health and Medical Research Council, NHMRCNational Health and Medical Research Council, NHMRC: APP1141339, APP 1102752, APP 1145777108589‐001Swedish Foundation for International Cooperation in Research and Higher Education, STINTCalifornia Department of Fish and Game, DFG: LE 3260/3‐1U.S. Department of Health and Human Services, HHSSwedish Foundation for International Cooperation in Research and Higher Education, STINTNational Institutes of Health, NIH: R01 CA 202021‐01‐A1CancerfondenVictorian Cancer Agency, VCA: MCRF18017, MCRF16007
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