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


  • K. Wethmar
  • V. Bégay
  • J.J. Smink
  • K. Zaragoza
  • V. Wiesenthal
  • B. Doerken
  • C.F. Calkhoven
  • A. Leutz


  • Genes & Development


  • Genes Dev 24 (1): 15-20


  • 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.