1. A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation.
- Author
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Sievert H, Pällmann N, Miller KK, Hermans-Borgmeyer I, Venz S, Sendoel A, Preukschas M, Schweizer M, Boettcher S, Janiesch PC, Streichert T, Walther R, Hengartner MO, Manz MG, Brümmendorf TH, Bokemeyer C, Braig M, Hauber J, Duncan KE, and Balabanov S
- Subjects
- 3T3 Cells, Alleles, Animals, Caenorhabditis elegans, Cell Proliferation, Cellular Senescence, Disease Models, Animal, Embryo Loss metabolism, Embryo Loss pathology, Fibroblasts metabolism, Fibroblasts pathology, Gene Knockout Techniques, Hydroxylation, Lysine metabolism, Mice, Mixed Function Oxygenases metabolism, Oxidoreductases Acting on CH-NH Group Donors metabolism, Peptide Initiation Factors metabolism, Phenotype, Protein Biosynthesis, Proto-Oncogene Proteins c-myc metabolism, RNA-Binding Proteins metabolism, ras Proteins metabolism, Eukaryotic Translation Initiation Factor 5A, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Embryonic Development, Lysine analogs & derivatives, Mixed Function Oxygenases antagonists & inhibitors
- Abstract
The central importance of translational control by post-translational modification has spurred major interest in regulatory pathways that control translation. One such pathway uniquely adds hypusine to eukaryotic initiation factor 5A (eIF5A), and thereby affects protein synthesis and, subsequently, cellular proliferation through an unknown mechanism. Using a novel conditional knockout mouse model and a Caenorhabditis elegans knockout model, we found an evolutionarily conserved role for the DOHH-mediated second step of hypusine synthesis in early embryonic development. At the cellular level, we observed reduced proliferation and induction of senescence in 3T3 Dohh-/- cells as well as reduced capability for malignant transformation. Furthermore, mass spectrometry showed that deletion of DOHH results in an unexpected complete loss of hypusine modification. Our results provide new biological insight into the physiological roles of the second step of the hypusination of eIF5A. Moreover, the conditional mouse model presented here provides a powerful tool for manipulating hypusine modification in a temporal and spatial manner, to analyse both how this unique modification normally functions in vivo as well as how it contributes to different pathological conditions., (© 2014. Published by The Company of Biologists Ltd.)
- Published
- 2014
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