Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling

Templin, Andrew T.; Maier, Bernhard; Nishiki, Yurika; Tersey, Sarah A.; Mirmira, Raghavendra G.

doi:10.4161/cc.10.7.15206

Cited by 24 publications

(31 citation statements)

References 38 publications

(39 reference statements)

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“…3A). This observation is well in line with data obtained in a mixed background published by others (43,44). Heterozygous Dhs ϩ/Ϫ animals were viable and did not show any obvious phenotype.…”

Section: Dhs Is Crucial For Embryonic Development As Well As For Viabsupporting

confidence: 82%

“…Therefore, we propose that a pharmacological inhibition of the hypusine-modifying enzymes below a level that is required for tumor cell proliferation and disease progression might represent a reliable therapeutic intervention. Interestingly, the concept of submaximal inhibition of hypusine synthesis has been suggested recently for inflammatory diseases (44). However, further studies to define the correct therapeutic index are needed to prevent devastating effects on normal homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…Mice-To study the biological relevance and functional requirement of the hypusine modification in embryonic development (43,44) and for viability, we used a recently described conditional knock-out strain for Dohh (33) and established a new conditional knock-out mouse model for Dhs (B6.Dhps tm2a(EUCOMM)Wtsi ). For the generation of the latter strain, embryonic stem cell clones were obtained from the International Knock-out Mouse Consortium (30).…”

Section: Dhs Is Crucial For Embryonic Development As Well As For Viabmentioning

confidence: 99%

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Biological Relevance and Therapeutic Potential of the Hypusine Modification System

Pällmann

Braig

Sievert

et al. 2015

Journal of Biological Chemistry

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Background: Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) represents a conserved post-translational modification that regulates translation. Results: Deletion of hypusine modification enzymes exerts strong phenotypes. eIF-5A2-deleted animals are viable and fertile. Conclusion: Both enzymatic steps of hypusine modification are essential for mammalian homeostasis, whereas the cancerrelated isoform eIF-5A2 is dispensable. Significance: eIF-5A2 might represent a safe therapeutic target.

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Section: Dhs Is Crucial For Embryonic Development As Well As For Viabsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Dhs Is Crucial For Embryonic Development As Well As For Viabmentioning

confidence: 99%

See 1 more Smart Citation

Biological Relevance and Therapeutic Potential of the Hypusine Modification System

Pällmann

Braig

Sievert

et al. 2015

Journal of Biological Chemistry

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“…The generation of knockout mice of eIF5A1, Dhps or Dohh revealed that all three are essential for early embryogenesis, whereas heterozygous mice are viable and fertile (Nishimura et al 2012; Pallmann et al 2015; Sievert et al 2014; Templin et al 2011); thus, hypusination of eIF5A1 is essential for survival and development of mammals. Interestingly, homozygous eIF5A2 knockout mice are viable and fertile (Pallmann et al 2015).…”

Section: Roles Of Hypusination In Cell Growth and Tumor Developmentmentioning

confidence: 99%

“…Furthermore, hypusinated eIF5A regulates the levels of inducible nitric oxide synthase and pharmacological inhibition of hypusination or depletion of eIF5A protects against glucose intolerance in inflammatory mouse models of diabetes (Maier et al 2010; Robbins et al 2010). Finally, Dhps heterozygosity attenuates acute cytokine signaling in mice (Templin et al 2011). Thus, targeting hypusine pathway can also impair the inflammatory response, which is a known driver of tumor progression (Lasry et al 2016).…”

Section: Hypusine and Other Diseasesmentioning

confidence: 99%

Targeting the polyamine-hypusine circuit for the prevention and treatment of cancer

Nakanishi

Cleveland

2016

Amino Acids

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The unique amino acid hypusine is present in only two proteins in eukaryotic cells, eukaryotic translation initiation factor 5A-1 (eIF5A1), and eIF5A2, where it is covalently linked to the lysine-50 residue of these proteins via a post-translational modification coined hypusination. This unique modification is directed by two highly conserved and essential enzymes, deoxyhypusine synthase (DHPS), and deoxyhypusine hydroxylase (DOHH), which selectively use the polyamine spermidine as a substrate to generate hypusinated eIF5A. Notably, elevated levels of polyamines are a hallmark of most tumor types, and increased levels of polyamines can also be detected in the urine and blood of cancer patients. Further, in-clinic agents that block the function of key biosynthetic enzymes in the polyamine pathway markedly impair tumor progression and maintenance of the malignant state. Thus, the polyamine pathway is attractive as a prognostic, prevention and therapeutic target. As we review, recent advances in our understanding of the specific functions of hypusinated eIF5A and its role in tumorigenesis suggest that the polyamine-hypusine circuit is a high priority target for cancer therapeutics.

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Protective effects of polyamine depletion in mouse models of type 1 diabetes: implications for therapy

et al. 2013

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The underlying pathophysiology of type 1 diabetes involves autoimmune-mediated islet inflammation, leading to dysfunction and death of insulin-secreting islet β cells. Recent studies have shown that polyamines, which are essential for mRNA translation, cellular replication, and the formation of the hypusine modification of eIF5A may play an important role in the progression of cellular inflammation. To test a role for polyamines in type 1 diabetes pathogenesis, we administered the ornithine decarboxylase inhibitor difluoromethylornithine to 2 mouse models—the low dose streptozotocin model and the NOD model—to deplete intracellular polyamines, and administered streptozotocin to third model, which was haploinsufficient for the gene encoding the hypusination enzyme deoxyhypusine synthase. Subsequent development of diabetes and/or glucose intolerance was monitored. In the low dose streptozotocin mouse model, continuous difluoromethylornithine administration dose-dependently reduced the incidence of hyperglycemia and led to the preservation of β cell area, whereas in the NOD mouse model of autoimmune diabetes difluoromethylornithine reduced diabetes incidence by 50%, preserved β cell area and insulin secretion, led to reductions in both islet inflammation and potentially diabetogenic Th17 cells in pancreatic lymph nodes. Difluoromethylornithine treatment reduced hypusinated eIF5A levels in both immune cells and islets. Animals haploinsufficient for the gene encoding deoxyhypusine synthase were partially protected from hyperglycemia induced by streptozotocin. Collectively, these studies suggest that interventions that interfere with polyamine biosynthesis and/or eIF5A hypusination may represent viable approaches in the treatment of diabetes.

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Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling

Cited by 24 publications

References 38 publications

Biological Relevance and Therapeutic Potential of the Hypusine Modification System

Biological Relevance and Therapeutic Potential of the Hypusine Modification System

Targeting the polyamine-hypusine circuit for the prevention and treatment of cancer

Protective effects of polyamine depletion in mouse models of type 1 diabetes: implications for therapy

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