A novel mouse model for inhibition of DOHH mediated hypusine modification reveals crucial function for embryonic development, proliferation and oncogenic transformation
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A novel mouse model for inhibition of DOHH mediated hypusine modification reveals crucial function for embryonic development, proliferation and oncogenic transformation. / Sievert, Henning; Pällmann, Nora; Miller, Katharine K; Hermans-Borgmeyer, Irmgard; Venz, Simone; Sendoel, Ataman; Preukschas, Michael; Schweizer, Michaela; Böttcher, Steffen; Janiesch, P Christoph; Streichert, Thomas; Walther, Reinhard; Hengartner, Michael O; Manz, Markus G; Brümmendorf, Tim H; Bokemeyer, Carsten; Balabanov, Melanie; Hauber, Joachim; Duncan, Kent E; Balabanov, Stefan.
In: DIS MODEL MECH, 15.05.2014.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A novel mouse model for inhibition of DOHH mediated hypusine modification reveals crucial function for embryonic development, proliferation and oncogenic transformation
AU - Sievert, Henning
AU - Pällmann, Nora
AU - Miller, Katharine K
AU - Hermans-Borgmeyer, Irmgard
AU - Venz, Simone
AU - Sendoel, Ataman
AU - Preukschas, Michael
AU - Schweizer, Michaela
AU - Böttcher, Steffen
AU - Janiesch, P Christoph
AU - Streichert, Thomas
AU - Walther, Reinhard
AU - Hengartner, Michael O
AU - Manz, Markus G
AU - Brümmendorf, Tim H
AU - Bokemeyer, Carsten
AU - Balabanov, Melanie
AU - Hauber, Joachim
AU - Duncan, Kent E
AU - Balabanov, Stefan
PY - 2014/5/15
Y1 - 2014/5/15
N2 - The central importance of translational control by posttranslational 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, by mass spectrometry we observed 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 to manipulate hypusine modification in a temporal and spatial manner, both to analyze how this unique modification normally functions in vivo, as well as how it contributes to different pathological conditions.
AB - The central importance of translational control by posttranslational 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, by mass spectrometry we observed 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 to manipulate hypusine modification in a temporal and spatial manner, both to analyze how this unique modification normally functions in vivo, as well as how it contributes to different pathological conditions.
U2 - 10.1242/dmm.014449
DO - 10.1242/dmm.014449
M3 - SCORING: Journal article
C2 - 24832488
JO - DIS MODEL MECH
JF - DIS MODEL MECH
SN - 1754-8403
ER -