Sievert, Henning, Paellmann, Nora, Miller, Katharine K., Hermans-Borgmeyer, Irm, Venz, Simone, Sendoel, Ataman, Preukschas, Michael, Schweizer, Michaela, Boettcher, Steffen ORCID: 0000-0001-9937-0957, Janiesch, P. Christoph, Streichert, Thomas, Walther, Reinhard, Hengartner, Michael O., Manz, Markus G., Bruemmendorf, Tim H., Bokemeyer, Carsten, Braig, Melanie, Hauber, Joachim, Duncan, Kent E. and Balabanov, Stefan (2014). A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation. Dis. Model. Mech., 7 (8). S. 963 - 977. CAMBRIDGE: COMPANY OF BIOLOGISTS LTD. ISSN 1754-8411

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Sievert, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paellmann, NoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miller, Katharine K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hermans-Borgmeyer, IrmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venz, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sendoel, AtamanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Preukschas, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweizer, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boettcher, SteffenUNSPECIFIEDorcid.org/0000-0001-9937-0957UNSPECIFIED
Janiesch, P. ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Streichert, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walther, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hengartner, Michael O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manz, Markus G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruemmendorf, Tim H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bokemeyer, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braig, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauber, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duncan, Kent E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balabanov, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-432249
DOI: 10.1242/dmm.014449
Journal or Publication Title: Dis. Model. Mech.
Volume: 7
Number: 8
Page Range: S. 963 - 977
Date: 2014
Publisher: COMPANY OF BIOLOGISTS LTD
Place of Publication: CAMBRIDGE
ISSN: 1754-8411
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
YEAST SACCHAROMYCES-CEREVISIAE; INITIATION-FACTOR 5A; AMINO-ACID-RESIDUES; ELONGATION-FACTOR P; FACTOR EF-P; TRANSLATION INITIATION; PROTEIN-SYNTHESIS; DEOXYHYPUSINE HYDROXYLASE; CAENORHABDITIS-ELEGANS; CELL-CYCLEMultiple languages
Cell Biology; PathologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43224

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