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Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE236087 | GEO | 2024/10/04

REPOSITORIES: GEO

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Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (scRNA-Seq)

Project description:Lung metastases are detected in more than half of patients with metastatic tumors. However, it remains largely unknown why the lung environment is a permissive niche for metastases. Here, we discover that pulmonary aspartate triggers a cellular signaling cascade in disseminated cancer cells resulting in a translational program that boosts lung metastasis. Specifically, we observe that patients and mice with breast cancer have high concentrations of aspartate in their lung interstitial fluid. This extracellular aspartate activates the ionotropic N-methyl-D-aspartate (NMDA) receptor in cancer cells, which induces CREB-dependent mRNA expression of deoxyhypusine hydroxylase (DOHH). The latter is essential for hypusination, a posttranslational modification required for the activity of the non-classical translation initiation factor eIF5A. In turn, a translational program with TGF-β signaling as a central hub promotes collagen remodeling in the disseminated breast cancer cells. We detect key aspects of this mechanism in lung metastases from patients with breast cancer. In summary, we discover that pulmonary aspartate increases with breast cancer and induces a signaling cascade promoting the growth of lung metastases.

2024-10-04 | GSE236084 | GEO

Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (Polysomal RNA-Seq)

2024-10-04 | GSE236086 | GEO

Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (Total RNA-Seq)

2024-10-04 | GSE277634 | GEO

Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation

Project description:Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation

| PRJNA988804 | ENA

Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (scRNA-Seq)

Project description:Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (scRNA-Seq)

| PRJNA988806 | ENA

Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (Polysomal RNA-Seq)

Project description:Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (Polysomal RNA-Seq)

| PRJNA988807 | ENA

Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (Total RNA-Seq)

Project description:Aspartate signaling increases the aggressiveness of lung metastases by inducing eIF5A-mediated translation (Total RNA-Seq)

| PRJNA1163021 | ENA

Regulation of gene expression by translation factor eIF5A: Hypusine-modified eIF5A enhances nonsense-mediated mRNA decay in human cells.

Project description:Nonsense-mediated mRNA decay (NMD) couples protein synthesis to mRNA turnover. It eliminates defective transcripts and controls the abundance of certain normal mRNAs. Our study establishes a connection between NMD and the translation factor eIF5A (eukaryotic initiation factor 5A) in human cells. eIF5A modulates the synthesis of groups of proteins (the eIF5A regulon), and undergoes a distinctive two-step post-translational modification (hypusination) catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase. We show that expression of NMD-susceptible constructs was increased by depletion of the major eIF5A isoform, eIF5A1. NMD was also attenuated when hypusination was inhibited by RNA interference with either of the two eIF5A modifying enzymes, or by treatment with the drugs ciclopirox or deferiprone which inhibit deoxyhypusine hydroxylase. Transcriptome analysis by RNA-Seq identified human genes whose expression is coordinately regulated by eIF5A1, its modifying enzymes, and the pivotal NMD factor, Upf1. Transcripts encoding components of the translation system were highly represented, including some encoding ribosomal proteins controlled by alternative splicing coupled to NMD (AS-NMD). Our findings extend and strengthen the association of eIF5A with NMD, previously inferred in yeast, and show that hypusination is important for this function of human eIF5A. In addition, they advance drug-mediated NMD suppression as a therapeutic opportunity for nonsense-associated diseases. We propose that regulation of mRNA stability contributes to eIF5A's role in selective gene expression.

| S-EPMC5630042 | biostudies-literature

The hypusine-containing translation factor eIF5A.

Project description:In addition to the small and large ribosomal subunits, aminoacyl-tRNAs, and an mRNA, cellular protein synthesis is dependent on translation factors. The eukaryotic translation initiation factor 5A (eIF5A) and its bacterial ortholog elongation factor P (EF-P) were initially characterized based on their ability to stimulate methionyl-puromycin (Met-Pmn) synthesis, a model assay for protein synthesis; however, the function of these factors in cellular protein synthesis has been difficult to resolve. Interestingly, a conserved lysine residue in eIF5A is post-translationally modified to hypusine and the corresponding lysine residue in EF-P from at least some bacteria is modified by the addition of a ?-lysine moiety. In this review, we provide a summary of recent data that have identified a novel role for the translation factor eIF5A and its hypusine modification in the elongation phase of protein synthesis and more specifically in stimulating the production of proteins containing runs of consecutive proline residues.

| S-EPMC4183722 | biostudies-literature

eIF5A promotes translation of polyproline motifs.

Project description:Translation factor eIF5A, containing the unique amino acid hypusine, was originally shown to stimulate Met-puromycin synthesis, a model assay for peptide bond formation. More recently, eIF5A was shown to promote translation elongation; however, its precise requirement in protein synthesis remains elusive. We use in vivo assays in yeast and in vitro reconstituted translation assays to reveal a specific requirement for eIF5A to promote peptide bond formation between consecutive Pro residues. Addition of eIF5A relieves ribosomal stalling during translation of three consecutive Pro residues in vitro, and loss of eIF5A function impairs translation of polyproline-containing proteins in vivo. Hydroxyl radical probing experiments localized eIF5A near the E site of the ribosome with its hypusine residue adjacent to the acceptor stem of the P site tRNA. Thus, eIF5A, like its bacterial ortholog EFP, is proposed to stimulate the peptidyl transferase activity of the ribosome and facilitate the reactivity of poor substrates like Pro.

| S-EPMC3744875 | biostudies-literature

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