PreprintCited by 47Estrogen and related hormone effectsRNA and protein synthesis mechanismsRNA Research and Splicing

Estrogen receptor alpha controls gene expression via translational offsetting

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Lorent, Julie, Rebello, Richard J., Hoef, Vincent van, Lawrence, Mitchell G., Szkop, Krzysztof J., Kusnadi, Eric, Samreen, Baila, Balanathan, Preetika +7 more·2018·The EMBO Journal

Preprint — published as 10.15252/embj.2018101323 · Paper page

Abstract

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 mRNA and 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 translational 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-modification enzymes, whereas altered expression of U34-modification enzymes disrupts ERα dependent translational offsetting. Altogether, we unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs, and highlight that translational offsetting may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.

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Authors
Lorent, J., Rebello, R. J., Hoef, V. V., Lawrence, M. G., Szkop, K. J., Kusnadi, E., Samreen, B., Balanathan, P., Scharmann, K., Takizawa, I., Leidel, S. A., Risbridger, G. P., Topisirovic, I., Larsson, O., & Furic, L.
Affiliations
  • Science for Life Laboratory (SE)
  • Peter MacCallum Cancer Centre (AU)
  • The University of Melbourne (AU)
  • Monash University (AU)
  • University of Münster (DE)
  • University of Bern (CH)
Corresponding author
  • Larsson, Ola
  • Furic, Luc
Venue
The EMBO Journal
Publisher
openRxiv
Published
2018-12-28
Volume
38
Issue
23
Pages
e101323-e101323
ISSN
0261-4189 (ISSN-L)
OpenAlex
W2975051965
Cited by
46
References
97
Citations by year
2026: 5 · 2025: 4 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 2 · 2018: 1
FWCI
3.16
Type
journal article
Language
en
Open access
Locations
  • The EMBO Journal (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • ORBi (University of Liège) (submittedVersion)
Funders
  • U.S. Department of Health and Human Services
  • Victorian Cancer Agency (MCRF16007)
  • Marshfield Clinic Research Foundation
  • Department of Health and Human Services, State Government of Victoria (MCRF16007, MCRF18017)
  • Government of Canada (MOP-363027)
  • Deutsche Forschungsgemeinschaft (LE 3260/3-1)
  • Swedish Foundation for International Cooperation in Research and Higher Education (IG2012-2073)
  • Cancerfonden (2016/526)
  • Karolinska Institutet
  • Knut och Alice Wallenbergs Stiftelse (2013.0181)
  • Vetenskapsrådet (2016-02891)
  • Cancerföreningen i Stockholm (151153)
  • Science for Life Laboratory
  • Walloon excellence in life sciences and biotechnology
  • National Institutes of Health
  • Canadian Institutes of Health Research (MOP-363027)
  • Fonds de Recherche du Québec - Santé (34872)
  • National Health and Medical Research Council (1145777, 1102752, 1141339)
  • National Cancer Institute (R01CA202021)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
estrogen receptor alpha, mRNA translation, transcriptional regulation, tRNA modification enzymes, microRNA binding sites, polysome association, hormone-dependent tumors, tumor cell proliferation
MeSH terms
Breast Neoplasms, Female, Humans, Polyribosomes, RNA, Messenger, Protein Biosynthesis, Signal Transduction, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Estrogen Receptor alpha, Cell Proliferation, MCF-7 Cells

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