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Essential role of eIF5A-1 and deoxyhypusine synthase in mouse embryonic development

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Abstract

The eukaryotic initiation factor 5A (eIF5A) contains a polyamine-derived amino acid, hypusine [Nε-(4-amino-2-hydroxybutyl)lysine]. Hypusine is formed post-translationally by the addition of the 4-aminobutyl moiety from the polyamine spermidine to a specific lysine residue, catalyzed by deoxyhypusine synthase (DHPS), and subsequent hydroxylation by deoxyhypusine hydroxylase (DOHH). The eIF5A precursor protein and both of its modifying enzymes are highly conserved, suggesting a vital cellular function for eIF5A and its hypusine modification. To address the functions of eIF5A and the first modification enzyme, DHPS, in mammalian development, we knocked out the Eif5a or the Dhps gene in mice. Eif5a heterozygous knockout mice and Dhps heterozygous knockout mice were viable and fertile. However, homozygous Eif5a1 gt/gt embryos and Dhps gt/gt embryos died early in embryonic development, between E3.5 and E7.5. Upon transfer to in vitro culture, homozygous Eif5a gt/gt or Dhps gt/gt blastocysts at E3.5 showed growth defects when compared to heterozygous or wild type blastocysts. Thus, the knockout of either the eIF5A-1 gene (Eif5a) or of the deoxyhypusine synthase gene (Dhps) caused early embryonic lethality in mice, indicating the essential nature of both eIF5A-1 and deoxyhypusine synthase in mammalian development.

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Abbreviations

eIF5A:

Eukaryotic translation initiation factor 5A

DHPS:

Deoxyhypusine synthase

DOHH:

Deoxyhypusine hydroxylase

Eif5a :

Mouse gene encoding eIF5A-1

Eif5a2 :

Mouse gene encoding the eIF5A-2 isoform

ES cells:

Embryonic stem cells

TCA:

Trichloroacetic acid

DTT:

Dithiothreitol

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Acknowledgments

The research was supported in part by the Intramural Research Program of National Institute of Dental and Craniofacial Research (NIDCR) NIH and KANAE Foundation for the Promotion of Medical Science (Japan). We thank Dr. Edith C. Wolff (NIDCR, NIH) for critical reading of the manuscript and helpful suggestions.

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Author notes

  1. Kazuhiro Nishimura

    Present address: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana Chuo-ku, Chiba, 260-8675, Japan

Authors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, NIDCR, National Institutes of Health, Bldg 30, Room 211, Bethesda, MD, 20892-4340, USA

    Kazuhiro Nishimura, Seung Bum Lee, Jong Hwan Park & Myung Hee Park

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  1. Kazuhiro Nishimura
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  2. Seung Bum Lee
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  3. Jong Hwan Park
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Correspondence to Myung Hee Park.

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Nishimura, K., Lee, S.B., Park, J.H. et al. Essential role of eIF5A-1 and deoxyhypusine synthase in mouse embryonic development. Amino Acids 42, 703–710 (2012). https://doi.org/10.1007/s00726-011-0986-z

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  • DOI: https://doi.org/10.1007/s00726-011-0986-z

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