title: C/EBPbetaDeltauORF mice--a genetic model for uORF-mediated translational control in mammals.
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.
authors.affiliation: Max Delbrück Center for Molecular Medicine, D-13092 Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Wethmar
authors.forename: Valérie
authors.initials: V
authors.lastname: Bégay
authors.forename: Jeske J
authors.initials: JJ
authors.lastname: Smink
authors.forename: Katrin
authors.initials: K
authors.lastname: Zaragoza
authors.forename: Volker
authors.initials: V
authors.lastname: Wiesenthal
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Cornelis F
authors.initials: CF
authors.lastname: Calkhoven
authors.forename: Achim
authors.initials: A
authors.lastname: Leutz
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D023421:Models, Animal; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta