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The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [RNA-seq]

ABSTRACT: Hypusinated EiF5A likely impacts diverse cellular pathways, through direct regulation of its translational targets or via secondary effects on other biological processes. We examined the global effects of knockdown of EiF5A and Dhps on the transcriptome and translational landscape of MYC-induced lymphoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE190669 | GEO | 2022/12/31

REPOSITORIES: GEO

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The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [Ribo-seq]

Project description:Hypusinated EiF5A likely impacts diverse cellular pathways through direct regulation of its translational targets or via secondary effects on other biological processes. We examined the global effects of knockdown of EiF5A and Dhps on the transcriptome and translational landscape of MYC-induced lymphoma.

2022-12-31 | GSE190670 | GEO

The polyamine-hypusine circuit controls an oncogenic translational program necessary for MYC-driven lymphomagenesis

Project description:MYC oncogenes are activated in broad spectrum of human malignancies and transcriptionally reprogram the genome to drive cancer cell growth. Given this it is unclear if targeting a single effector will have a therapeutic benefit. MYC activates the polyaminehypusine circuit, which post-translationally modifies the translation factor eIF5A. The hypusine axis has been proposed to suppress tumorigenesis. Here we report essential roles for hypusinated eIF5A in the development and maintenance of Myc-driven lymphoma, where loss of eIF5A hypusination abolishes malignant transformation. Mechanistically, integrating RNA-seq, Ribo-seq and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including key regulators of G1 to S phase cell cycle progression. Notably, this circuit controls Myc’s proliferative response at several levels, and it is activated across multiple tumor types. These findings suggest the hypusine circuit as a therapeutic target for a broad spectrum of malignancies.

2024-01-26 | PXD031361 | Pride

Organogenesis and replication phenoypes in vivo suggest distinct effects of hypusinated and unhypusinated eIF5A

Project description:Prior to type 2 diabetes onset, β cells adapt to insulin resistance through compensation—a process that maintains insulin secretion and glucose homeostasis. Our lab has previously shown that β cell compensation requires the activity of deoxyhypusine synthase (DHPS), which post-translationally catalyzes the formation of the amino acid hypusine at Lys50 of eukaryotic initiation factor eIF5A. Although hypusinated eIF5A is required for β cell compensation, it is unclear if unhypusinated eIF5A limits this compensatory response. To identify the role of unhypusinated eIF5A, we used the following animal and cell-based models: transgenic zebrafish and inducible, β cell-specific knockout mice fed a high fat diet. Zebrafish embryos injected with morpholinos to reduce global DHPS (and accumulate unhypusinated eIF5A) showed stunted exocrine pancreas growth at 3 days post-fertilization. Although, those injected with anti-eIF5A morpholinos (to deplete all eIF5A) showed normal pancreas growth. Although a unique function of unhypusinated eIF5A has not yet been documented, these findings suggest that the presence of unhypusinated eIF5A may be the major driver of altered pancreas phenotypes. Similarly, following 4 weeks of high fat diet feeding and obesity, mice lacking total eIF5A in β cells had improved glucose tolerance compared to mice lacking DHPS in β cells, despite similar weight gain and insulin sensitivity. Taken together, our data provide evidence that DHPS deficiency and obesity conditions impair β cell function, inpart, from the accumulation of the unhypusinated form of eIF5A. Our studies reveal a mechanism in which β cells respond to obesity by regulating mRNA translation through the balance between hypusinated and unhypusinated forms of eIF5A.

2024-10-27 | GSE279773 | GEO

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-31 | GSE190671 | GEO

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis

Project description:The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis

| PRJNA787942 | ENA

Hypusine Biosynthesis in β Cells Links Polyamine Metabolism to Facultative Cellular Proliferation to Maintain Glucose Homeostasis

Project description:Deoxyhypusine synthase (DHPS) utilizes the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly-defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that allows for inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β-cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation, reduced production of the cell cycle molecule Cyclin D2, impaired β-cell proliferation, and overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

2019-08-30 | GSE136581 | GEO

Deoxyhypusine synthase (DHPS) mutations alter the post-translational modification of eukaryotic initiation factor 5A (eIF5A) resulting in impaired human and mouse neural homeostasis

Project description:DHPS deficiency is a rare genetic disease caused by biallelic hypomorphic variants in the Deoxyhypusine synthase (DHPS) gene. The DHPS enzyme functions in mRNA translation by catalyzing the post-translational modification, and therefore activation, of the eukaryotic initiation factor 5A (eIF5A). The observed clinical outcomes associated with human mutations in DHPS include developmental delay, intellectual disability, and seizures. Therefore, to increase our understanding of this rare disease, it is critical to determine the mechanisms by which mutations in DHPS alter neurodevelopment. In this study, we have generated patient-derived lymphoblast cell lines and demonstrated that human DHPS variants alter DHPS protein abundance and impair enzyme function. Moreover, we observe a shift in the abundance of the post-translationally modified forms of eIF5A, specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP). Generation and characterization of a mouse model with a genetic deletion of Dhps in the brain at birth shows that loss of hypusine biosynthesis impacts neuronal function due to impaired eIF5AHYP-dependent mRNA translation; this translation defect results in altered expression of proteins required for proper neuronal development and function. This study reveals new insight into the biological consequences and molecular impact of human DHPS deficiency and provides valuable information towards the goal of developing treatment strategies for this rare disease.

2023-06-06 | MSV000092112 | MassIVE

Hypusination Orchestrates the Antimicrobial Response of Macrophages

Project description:Innate responses of myeloid cells defend against pathogenic bacteria via inducible effectors. Deoxyhypusine synthase (DHPS) catalyzes the transfer of the N-moiety of spermidine to the lysine-50 residue of eukaryotic translation initiation factor 5A (EIF5A) to form the amino acid hypusine. Hypusinated EIF5A (EIF5AHyp) transports specific mRNAs to ribosomes for translation. We show that DHPS is induced in macrophages by two gastrointestinal pathogens, Helicobacter pylori and Citrobacter rodentium, resulting in enhanced hypusination of EIF5A. EIF5AHyp was also increased in gastric macrophages from patients with H. pylori gastritis. Furthermore, we identify the bacteria-induced immune effectors regulated by hypusination. This set of proteins includes essential constituents of antimicrobial response and autophagy. Mice with myeloid cell-specific deletion of Dhps exhibit reduced EIF5AHyp in macrophages and increased bacterial burden and inflammation. Thus, regulation of translation through hypusination is a critical hallmark of the defense of eukaryotic hosts against pathogenic bacteria.

2021-04-06 | MTBLS607 | MetaboLights

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [Ribo-seq]

Project description:The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [Ribo-seq]

| PRJNA787943 | ENA

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [RNA-seq]

Project description:The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [RNA-seq]

| PRJNA787944 | ENA