PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Estrogen receptor alpha controls gene expression via translational offsetting
Julie Lorent 1 , Richard J Rebello 2, , Vincent van Hoef 1 , Mitchell G Lawrence 2, , Krzysztof J Szkop 1 , Eric Kusnadi 2 , Baila Samreen 1 , Preetika Balanathan 3 , Karin Scharmann 5, , Itsuhiro Takizawa 3 , Sebastian A Leidel 5, , Gail P Risbridger 2, , Ivan Topisirovic 8 , Ola Larsson 1 & Luc Furic 2,
1Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Stockholm, Sweden; 2Prostate Cancer Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia; 3Cancer Program, Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia; 4Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia; 5Max Planck Institute for Molecular Biomedicine, Münster, Germany; 6Cells-in-Motion Cluster of Excellence, University of Münster, Münster, Germany; 7Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland; 8Lady Davis Institute, Gerald Bronfman Department of Oncology and Departments of Biochemistry and Experimental Medicine, McGill University, Montreal, QC, H3T1E2, Canada.
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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Oncology Abstracts
ISSN 2631-4657 (online)
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