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: Klaus Wethmar, Valérie Bégay, Jeske J Smink, Katrin Zaragoza, Volker Wiesenthal, Bernd Dörken, Cornelis F Calkhoven, Achim Leutz
• Journal: Genes & development (Genes Dev) Vol. 24 Issue 1 Pg. 15-20 (Jan 01 2010) ISSN: 1549-5477 [Electronic] United States
• PMID: 20047998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCAAT-Enhancer-Binding Protein-beta

Topics

• 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)