Biological Relevance and Therapeutic Potential of the Hypusine Modification System

Pällmann, Nora; Braig, Melanie; Sievert, Henning; Preukschas, Michael; Hermans‐Borgmeyer, Irm; Schweizer, Michaela; Nagel, Claus Henning; Neumann, Melanie; Wild, Peter J.; Haralambieva, Eugenia; Hagel, Christian; Bokemeyer, Carsten; Hauber, Joachim; Balabanov, Stefan

doi:10.1074/jbc.m115.664490

Cited by 54 publications

(60 citation statements)

References 95 publications

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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%

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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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Section: Roles Of Hypusination In Cell Growth and Tumor Developmentmentioning

confidence: 99%

“…Interestingly, homozygous eIF5A2 knockout mice are viable and fertile (Pallmann et al 2015). Whether this is due to functional redundancy of eIF5A1 and eIF5A2 remains to be investigated.…”

Section: Roles Of Hypusination In Cell Growth and Tumor Developmentmentioning

confidence: 99%

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

Nakanishi

Cleveland

2016

Amino Acids

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“…We have recently observed that brusatol has a remarkable efficacy in protecting rat insulin-producing b cells against dysfunction and destruction induced by the proinflammatory cytokines IL-1b and IFN-g, and that this possibly occurred via inhibition of iNOS induction by a posttranscriptional mechanism (16). The biosynthesis of certain proteins is controlled by the translation factor eukaryotic initiation factor 5A (eIF5A) (17). The unique hypusine modification of eIF5A, in which an aminobutyl moiety is transferred from spermidine to a lysine residue, is a crucial requirement for eIF5A translation of the specific mRNAs, i.e., mainly mRNAs containing proline-rich Pro-Pro-Pro (PPP) or Pro-Pro-Gly (PPG) sequences (18)(19)(20).…”

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confidence: 99%

The protein synthesis inhibitor brusatol normalizes high‐fat diet‐induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination

et al. 2018

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The naturally occurring quassinoid compound brusatol improves the survival of insulin‐producing cells when exposed to the proinflammatory cytokines IL‐1β and IFN‐γ in vitro. The aim of the present study was to investigate whether brusatol also promotes beneficial effects in mice fed a high‐fat diet (HFD), and if so, to study the mechanisms by which brusatol acts. In vivo, we observed that the impaired glucose tolerance of HFD‐fed male C57BL/6 mice was counteracted by a 2 wk treatment with brusatol. Brusatol treatment improved both β‐cell function and peripheral insulin sensitivity of HFD‐fed mice. In vitro, brusatol inhibited β‐cell total protein and proinsulin biosynthesis, with an ED50 of ∼40 nM. In line with this, brusatol blocked cytokine‐induced iNOS protein expression via inhibition of iNOS mRNA translation. Brusatol may have affected protein synthesis, at least in part, via inhibition of eukaryotic initiation factor 5A (eIF5A) hypusination, as eIF5A spermidine association and hypusination in RIN‐5AH cells was reduced in a dose‐ and time‐dependent manner. The eIF5A hypusination inhibitor GC7 promoted a similar effect. Both brusatol and GC7 protected rat RIN‐5AH cells against cytokine‐induced cell death. Brusatol reduced eIF5A hypusination and cytokine‐induced cell death in EndoC‐βHl cells as well. Finally, hypusinated eIF5A was reduced in vivo by brusatol in islet endocrine and endothelial islet cells of mice fed an HFD. The results of the present study suggest that brusatol improves glucose intolerance in mice fed an HFD, possibly by inhibiting protein biosynthesis and eIF5A hypusination.—Turpaev, K., Krizhanovskii, C., Wang, X., Sargsyan, E., Bergsten, P., Welsh, N. The protein synthesis inhibitor brusatol normalizes high‐fat diet‐induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination. FASEB J. 33, 3510–3522 (2019). http://www.fasebj.org

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“…Proteins containing such proline repeats include proteins regulating key functions in growth and development including actin/cytoskeleton-associated functions, RNA splicing/turnover, DNA binding/transcription, and cell signaling (27,33). eIF5A is a relatively stable protein, but it can be acetylated either at Lys 47 (a residue essential for activity) by certain histone acetyltransferases or on the deoxyhypusine residue by SSAT (34), suggesting that its function may be regulated by acetylation/deacetylation.…”

Section: Hypusine and Eif5amentioning

confidence: 99%

“…Vertebrates have a second gene encoding eIF5A2, which is not widely expressed and is not essential but is present in several cancers where it is associated with aggressive growth and a poor prognosis (27,29). Prevention of hypusine formation in eIF5A2 inhibits tumor growth and reduces expression of the oncogenic tyrosine kinase PEAK1 (35).…”

Section: Hypusine and Eif5amentioning

confidence: 99%

Functions of Polyamines in Mammals

Pegg

2016

Journal of Biological Chemistry

536

428

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The content of spermidine and spermine in mammalian cells has important roles in protein and nucleic acid synthesis and structure, protection from oxidative damage, activity of ion channels, cell proliferation, differentiation, and apoptosis. Spermidine is essential for viability and acts as the precursor of hypusine, a post-translational addition to eIF5A allowing the translation of mRNAs encoding proteins containing polyproline tracts. Studies with Gy mice and human patients with the very rare X-linked genetic condition Snyder-Robinson syndrome that both lack spermine synthase show clearly that the correct spermine:spermidine ratio is critical for normal growth and development.There is very strong experimental evidence that maintenance of a normal polyamine content is essential for a wide variety of basic cellular functions. (a) Their content is very tightly controlled with the key enzymes in biosynthesis and interconversion having multiple levels of regulation in response to hormonal stimulation and polyamine content. (b) With the use of specific inhibitors of polyamine biosynthesis, it is relatively easy to substantially deplete cellular polyamine content, and striking effects have been observed on numerous critical cell functions including growth, differentiation, apoptosis, motility, and resistance to oxidative and other stresses. (c) The interaction of polyamines with nucleic acids and proteins can affect both structure and stability. Binding of polyamines to DNA affects its structure and stability (1). The importance of the effects on DNA stability is emphasized by the presence in acute thermophiles of high levels of polyamines, including branched chain molecules and longer linear amines than those found in mammals. These allow their survival at elevated temperatures (2). The majority of cellular polyamines are bound to RNA, and the changes in structure produced by binding to ribosomes, tRNA, and some mRNAs with particular sequences influence protein synthesis in multiple ways (3). Interactions of polyamines with proteins forming microtubules can influence their assembly and shape (4), and interaction with protein membrane receptors can have profound effects on crucial receptors.It should be stressed that these observations, although confirming that polyamines are essential cellular components, do not indicate that the polyamines necessarily play regulatory roles. Experimental support for such regulation would require the demonstration that physiological rather than pharmacological changes in polyamine content are associated with alterations in function, and this has rarely been demonstrated rigorously.It is not possible in a brief review to describe all of the actions that have been assigned to polyamines. The focus is on those functions that have been demonstrated to influence animal growth and development with particular emphasis on the phenotypes revealed by experimental animals and humans with an inborn error of metabolism leading to a reduction in spermine.

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Biological Relevance and Therapeutic Potential of the Hypusine Modification System

Cited by 54 publications

References 95 publications

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

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

The protein synthesis inhibitor brusatol normalizes high‐fat diet‐induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination

Functions of Polyamines in Mammals

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