C/EBPbetaDeltauORF mice--a genetic model for uORF-mediated translational control in mammals

Klaus Wethmar; Valérie Bégay; Jeske J Smink; Katrin Zaragoza; Volker Wiesenthal; Bernd Dörken; Cornelis F Calkhoven; Achim Leutz

doi:10.1101/gad.557910

C/EBPbetaDeltauORF mice--a genetic model for uORF-mediated translational control in mammals

Genes Dev. 2010 Jan 1;24(1):15-20. doi: 10.1101/gad.557910.

Authors

Klaus Wethmar¹, Valérie Bégay, Jeske J Smink, Katrin Zaragoza, Volker Wiesenthal, Bernd Dörken, Cornelis F Calkhoven, Achim Leutz

Affiliation

¹ Max Delbrück Center for Molecular Medicine, D-13092 Berlin, Germany.

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 beta (C/EBPbeta) uORF initiation codon fail to initiate translation of the autoantagonistic LIP (liver inhibitory protein) C/EBPbeta isoform. C/EBPbeta(DeltauORF) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CCAAT-Enhancer-Binding Protein-beta / genetics*
Cell Cycle / genetics
Female
Gene Expression Regulation*
Liver / metabolism
Male
Mice
Models, Animal*
Mutation
Open Reading Frames / genetics*

Substances

CCAAT-Enhancer-Binding Protein-beta