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• W647485572 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 knock-out mouse models for the hypusine-modifying enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase as well as for the cancer-related isoform eIF-5A2. We discovered that homozygous depletion of deoxyhypusine synthase and/or deoxyhypusine hydroxylase causes lethality in adult mice with different penetrance compared with 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 the 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 with lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer. 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 knock-out mouse models for the hypusine-modifying enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase as well as for the cancer-related isoform eIF-5A2. We discovered that homozygous depletion of deoxyhypusine synthase and/or deoxyhypusine hydroxylase causes lethality in adult mice with different penetrance compared with 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 the 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 with lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer." @default.
• W647485572 created "2016-06-24" @default.
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• W647485572 date "2015-07-01" @default.
• W647485572 modified "2023-10-09" @default.
• W647485572 title "Biological Relevance and Therapeutic Potential of the Hypusine Modification System" @default.
• W647485572 cites W1506072704 @default.
• W647485572 cites W1753315956 @default.
• W647485572 cites W1896910541 @default.
• W647485572 cites W1968202347 @default.
• W647485572 cites W1968423742 @default.
• W647485572 cites W1968682237 @default.
• W647485572 cites W1968779484 @default.
• W647485572 cites W1968963646 @default.
• W647485572 cites W1974347350 @default.
• W647485572 cites W1976954198 @default.
• W647485572 cites W1980583054 @default.
• W647485572 cites W1981191264 @default.
• W647485572 cites W1982210988 @default.
• W647485572 cites W1982318323 @default.
• W647485572 cites W1983788160 @default.
• W647485572 cites W1985068260 @default.
• W647485572 cites W1987533090 @default.
• W647485572 cites W1988130829 @default.
• W647485572 cites W1989844355 @default.
• W647485572 cites W1990984319 @default.
• W647485572 cites W2000860171 @default.
• W647485572 cites W2001679453 @default.
• W647485572 cites W2002297354 @default.
• W647485572 cites W2003704622 @default.
• W647485572 cites W2005056727 @default.
• W647485572 cites W2009564945 @default.
• W647485572 cites W2012116939 @default.
• W647485572 cites W2014489014 @default.
• W647485572 cites W2016010426 @default.
• W647485572 cites W2019528668 @default.
• W647485572 cites W2019834045 @default.
• W647485572 cites W2022413799 @default.
• W647485572 cites W2033306225 @default.
• W647485572 cites W2034846070 @default.
• W647485572 cites W2039171339 @default.
• W647485572 cites W2041323674 @default.
• W647485572 cites W2041395895 @default.
• W647485572 cites W2042742511 @default.
• W647485572 cites W2043570667 @default.
• W647485572 cites W2045860277 @default.
• W647485572 cites W2047998870 @default.
• W647485572 cites W2050721857 @default.
• W647485572 cites W2057803077 @default.
• W647485572 cites W2059430774 @default.
• W647485572 cites W2059908550 @default.
• W647485572 cites W2060337869 @default.
• W647485572 cites W2061031248 @default.
• W647485572 cites W2061659241 @default.
• W647485572 cites W2062809474 @default.
• W647485572 cites W2067131315 @default.
• W647485572 cites W2071304232 @default.
• W647485572 cites W2074370114 @default.
• W647485572 cites W2074974586 @default.
• W647485572 cites W2081788726 @default.
• W647485572 cites W2090850633 @default.
• W647485572 cites W2091530153 @default.
• W647485572 cites W2092901172 @default.
• W647485572 cites W2094154815 @default.
• W647485572 cites W2094330276 @default.
• W647485572 cites W2096173332 @default.
• W647485572 cites W2096248890 @default.
• W647485572 cites W2097102109 @default.
• W647485572 cites W2102723674 @default.
• W647485572 cites W2103699686 @default.
• W647485572 cites W2106016335 @default.
• W647485572 cites W2107277218 @default.
• W647485572 cites W2108401385 @default.
• W647485572 cites W2121418284 @default.
• W647485572 cites W2123975270 @default.
• W647485572 cites W2127386189 @default.
• W647485572 cites W2128453465 @default.
• W647485572 cites W2129620576 @default.
• W647485572 cites W2130790725 @default.
• W647485572 cites W2133234260 @default.
• W647485572 cites W2134235310 @default.
• W647485572 cites W2136265964 @default.
• W647485572 cites W2136850043 @default.
• W647485572 cites W2140553945 @default.
• W647485572 cites W2142748510 @default.

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