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Biological Relevance and Therapeutic Potential of the Hypusine Modification System

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Biological Relevance and Therapeutic Potential of the Hypusine Modification System. / Pallmann, Nora; Braig, Melanie; Sievert, Henning; Preukschas, Michael; Hermans-Borgmeyer, Irm; Schweizer, Michaela; Nagel, Claus Henning; Neumann, Melanie; Wild, Peter; Haralambieva, Eugenia; Hagel, Christian; Bokemeyer, Carsten; Hauber, Joachim; Balabanov, Stefan.

in: J BIOL CHEM, Jahrgang 290, Nr. 30, 02.06.2015, S. 18343-18360.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Pallmann, N, Braig, M, Sievert, H, Preukschas, M, Hermans-Borgmeyer, I, Schweizer, M, Nagel, CH, Neumann, M, Wild, P, Haralambieva, E, Hagel, C, Bokemeyer, C, Hauber, J & Balabanov, S 2015, 'Biological Relevance and Therapeutic Potential of the Hypusine Modification System', J BIOL CHEM, Jg. 290, Nr. 30, S. 18343-18360. https://doi.org/10.1074/jbc.M115.664490

APA

Pallmann, N., Braig, M., Sievert, H., Preukschas, M., Hermans-Borgmeyer, I., Schweizer, M., Nagel, C. H., Neumann, M., Wild, P., Haralambieva, E., Hagel, C., Bokemeyer, C., Hauber, J., & Balabanov, S. (2015). Biological Relevance and Therapeutic Potential of the Hypusine Modification System. J BIOL CHEM, 290(30), 18343-18360. https://doi.org/10.1074/jbc.M115.664490

Vancouver

Pallmann N, Braig M, Sievert H, Preukschas M, Hermans-Borgmeyer I, Schweizer M et al. Biological Relevance and Therapeutic Potential of the Hypusine Modification System. J BIOL CHEM. 2015 Jun 2;290(30):18343-18360. https://doi.org/10.1074/jbc.M115.664490

Bibtex

@article{4d8aae6b04cb4bdd93c8f14566283582,
title = "Biological Relevance and Therapeutic Potential of the Hypusine Modification System",
abstract = "Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is emerging as a crucial regulator in cancer, infections and inflammation. Although its contribution in translational regulation of proline-repeat-rich proteins has been sufficiently demonstrated, its biological role in higher eukaryotes remains poorly understood. To establish the hypusine modification system as a novel platform for therapeutic strategies, we aimed to investigate its functional relevance in mammals by generating and using a range of new knockout mouse models for the hypusine modifying enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) as well as for the cancer-related isoform eIF-5A2. We uncovered that homozygous depletion of DHS or DOHH causes lethality in adult mice with different penetrance compared to haploinsufficiency. Network-based bioinformatic analysis of proline-repeat-rich proteins, which are putative eIF-5A targets, revealed that these proteins are organized in highly connected protein-protein-interaction networks. Hypusine-dependent translational control of essential proteins (hubs) and protein complexes inside these networks might explain the lethal phenotype observed after deletion of hypusine modifying enzymes. Remarkably, our results also demonstrate that the cancer-associated isoform eIF-5A2 is dispensable for normal development and viability. Together, our results provide first genetic evidence that the hypusine modification in eIF-5A is crucial for homeostasis in mammals. Moreover, these findings highlight functional diversity of the hypusine system compared to lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer.",
author = "Nora Pallmann and Melanie Braig and Henning Sievert and Michael Preukschas and Irm Hermans-Borgmeyer and Michaela Schweizer and Nagel, {Claus Henning} and Melanie Neumann and Peter Wild and Eugenia Haralambieva and Christian Hagel and Carsten Bokemeyer and Joachim Hauber and Stefan Balabanov",
note = "Copyright {\textcopyright} 2015, The American Society for Biochemistry and Molecular Biology.",
year = "2015",
month = jun,
day = "2",
doi = "10.1074/jbc.M115.664490",
language = "English",
volume = "290",
pages = "18343--18360",
journal = "J BIOL CHEM",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "30",

}

RIS

TY - JOUR

T1 - Biological Relevance and Therapeutic Potential of the Hypusine Modification System

AU - Pallmann, Nora

AU - Braig, Melanie

AU - Sievert, Henning

AU - Preukschas, Michael

AU - Hermans-Borgmeyer, Irm

AU - Schweizer, Michaela

AU - Nagel, Claus Henning

AU - Neumann, Melanie

AU - Wild, Peter

AU - Haralambieva, Eugenia

AU - Hagel, Christian

AU - Bokemeyer, Carsten

AU - Hauber, Joachim

AU - Balabanov, Stefan

N1 - Copyright © 2015, The American Society for Biochemistry and Molecular Biology.

PY - 2015/6/2

Y1 - 2015/6/2

N2 - Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is emerging as a crucial regulator in cancer, infections and inflammation. Although its contribution in translational regulation of proline-repeat-rich proteins has been sufficiently demonstrated, its biological role in higher eukaryotes remains poorly understood. To establish the hypusine modification system as a novel platform for therapeutic strategies, we aimed to investigate its functional relevance in mammals by generating and using a range of new knockout mouse models for the hypusine modifying enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) as well as for the cancer-related isoform eIF-5A2. We uncovered that homozygous depletion of DHS or DOHH causes lethality in adult mice with different penetrance compared to haploinsufficiency. Network-based bioinformatic analysis of proline-repeat-rich proteins, which are putative eIF-5A targets, revealed that these proteins are organized in highly connected protein-protein-interaction networks. Hypusine-dependent translational control of essential proteins (hubs) and protein complexes inside these networks might explain the lethal phenotype observed after deletion of hypusine modifying enzymes. Remarkably, our results also demonstrate that the cancer-associated isoform eIF-5A2 is dispensable for normal development and viability. Together, our results provide first genetic evidence that the hypusine modification in eIF-5A is crucial for homeostasis in mammals. Moreover, these findings highlight functional diversity of the hypusine system compared to lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer.

AB - Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is emerging as a crucial regulator in cancer, infections and inflammation. Although its contribution in translational regulation of proline-repeat-rich proteins has been sufficiently demonstrated, its biological role in higher eukaryotes remains poorly understood. To establish the hypusine modification system as a novel platform for therapeutic strategies, we aimed to investigate its functional relevance in mammals by generating and using a range of new knockout mouse models for the hypusine modifying enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) as well as for the cancer-related isoform eIF-5A2. We uncovered that homozygous depletion of DHS or DOHH causes lethality in adult mice with different penetrance compared to haploinsufficiency. Network-based bioinformatic analysis of proline-repeat-rich proteins, which are putative eIF-5A targets, revealed that these proteins are organized in highly connected protein-protein-interaction networks. Hypusine-dependent translational control of essential proteins (hubs) and protein complexes inside these networks might explain the lethal phenotype observed after deletion of hypusine modifying enzymes. Remarkably, our results also demonstrate that the cancer-associated isoform eIF-5A2 is dispensable for normal development and viability. Together, our results provide first genetic evidence that the hypusine modification in eIF-5A is crucial for homeostasis in mammals. Moreover, these findings highlight functional diversity of the hypusine system compared to lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer.

U2 - 10.1074/jbc.M115.664490

DO - 10.1074/jbc.M115.664490

M3 - SCORING: Journal article

C2 - 26037925

VL - 290

SP - 18343

EP - 18360

JO - J BIOL CHEM

JF - J BIOL CHEM

SN - 0021-9258

IS - 30

ER -