C/EBPβΔuORF mice—a genetic model for uORF-mediated translational control in mammals
- Klaus Wethmar1,2,
- Valérie Bégay1,5,
- Jeske J. Smink1,5,
- Katrin Zaragoza1,5,
- Volker Wiesenthal1,6,
- Bernd Dörken2,
- Cornelis F. Calkhoven3 and
- Achim Leutz1,4,7
- 1Max Delbrück Center for Molecular Medicine, D-13092 Berlin, Germany;
- 2Charité, Campus Virchow Klinikum, University Medicine Berlin, D-13353 Berlin, Germany;
- 3Leibniz Institute for Age Research–Fritz Lipmann Institute, D-07745 Jena, Germany;
- 4Department of Biology, Humboldt-University, D-10115 Berlin, Germany
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↵5 These authors contributed equally to this work.
Abstract
Upstream ORFs (uORFs) are translational control elements found predominantly in transcripts of key regulatory genes. No mammalian genetic model exists to experimentally validate the physiological relevance of uORF-regulated translation initiation. We report that mice deficient for the CCAAT/enhancer-binding protein β (C/EBPβ) uORF initiation codon fail to initiate translation of the autoantagonistic LIP (liver inhibitory protein) C/EBPβ isoform. C/EBPβΔuORF mice show hyperactivation of acute-phase response genes, persistent repression of E2F-regulated genes, delayed and blunted S-phase entry of hepatocytes after partial hepatectomy, and impaired osteoclast differentiation. These data and the widespread prevalence of uORFs in mammalian transcriptomes suggest a comprehensive role of uORF-regulated translation in (patho)physiology.
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Footnotes
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↵7 Corresponding author.
E-MAIL aleutz{at}mdc-berlin.de; FAX 49-30-9406-3298.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.557910.
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Supplemental material is available at http://www.genesdev.org.
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- Received May 11, 2009.
- Accepted October 30, 2009.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
