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

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

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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.

Originele taal-2	English
Pagina's (van-tot)	15-20
Aantal pagina's	6
Tijdschrift	Genes & Development
Volume	24
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1101/gad.557910
Status	Published - 1-jan.-2010
Extern gepubliceerd	Ja

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C/EBPβΔuORF mice—a genetic model for uORF-mediated translational control in mammalsFinal publisher's version, 865 KBLicentie: Unspecified

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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.",

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T1 - C/EBPbetaDeltauORF mice--a genetic model for uORF-mediated translational control in mammals

AU - Wethmar, Klaus

AU - Bégay, Valérie

AU - Smink, Jeske J.

AU - Zaragoza, Katrin

AU - Wiesenthal, Volker

AU - Dörken, Bernd

AU - Calkhoven, Cornelis F.

AU - Leutz, Achim

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

KW - Animals

KW - CCAAT-Enhancer-Binding Protein-beta

KW - Cell Cycle

KW - Female

KW - Gene Expression Regulation

KW - Liver

KW - Male

KW - Mice

KW - Models, Animal

KW - Mutation

KW - Open Reading Frames

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SP - 15

EP - 20

JO - Genes & Development

JF - Genes & Development

IS - 1

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

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