Inhibitor of prolyl-tRNA synthetase (PRS) to reduce tubulointerstitial nephritis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE213683 | GEO | 2022/09/24
REPOSITORIES: GEO
Similar Datasets
Project description:Glutamyl-prolyl-tRNA synthetase (EPRS) is a unique bifunctional aminoacyl-tRNA synthetase which catalyzes the ATP-dependent aminoacylation of glutamyl and prolyl residues to cognate tRNAs, constituting fundamental building blocks in protein synthesis. Genomic data suggest that EPRS promotes disease progression and is associated with poor prognosis in multiple myeloma (MM), while downregulation of EPRS triggers MM cell apoptosis implying an amino acid starvation response as a central mechanism. We developed a novel ATP competitive inhibitor, NCP26, targeting the prolyl-tRNA synthetase (PRS) component. The inhibitor demonstrates significant anti-tumor activity against human MM cell lines, regardless of their sensitivity to other therapeutic agents, against patient MM cells and is active in vivo using a MM xenograft mouse model. In contrast to the proline competitive PRS inhibitor halofuginone, NCP26 effects are not altered by exogenous proline levels. NCP26 treatment induces G0/G1 cell cycle arrest followed by apoptotic MM cell death, evidenced by depletion of mitochondrial membrane potential as well as caspase and PARP cleavage. Using combined transcriptomic and proteomic approaches we demonstrate a complex phenotypic response involving multiple pathways in protein quality control which center around the ribosome as integrating hub. Furthermore, we identified multiple proline rich motif containing protein targets of NCP26 as downstream effectors. These include myeloma survival factors such as syndecan 1 (SDC1, CD138), or basic helix-loop-helix transcription factors such as MYC, and transcription factor 3 (TCF3) suggesting that acute blockade of prolyl- aminoacylation evokes a complex pro-apoptotic response beyond the canonical amino acid starvation and integrated stress response. Taken together, our pre-clinical studies validate EPRS as a possible therapeutic target and provide the framework for evaluation of PRS inhibitors in a clinical setting.
2022-09-08 | GSE186445 | GEO
Project description:Glutamyl-prolyl-tRNA synthetase (EPRS) is a unique bifunctional aminoacyl-tRNA synthetase which catalyzes the ATP-dependent aminoacylation of glutamyl and prolyl residues to cognate tRNAs, constituting fundamental building blocks in protein synthesis. Genomic data suggest that EPRS promotes disease progression and is associated with poor prognosis in multiple myeloma (MM), while downregulation of EPRS triggers MM cell apoptosis implying an amino acid starvation response as a central mechanism. We developed a novel ATP competitive inhibitor, NCP26, targeting the prolyl-tRNA synthetase (PRS) component. The inhibitor demonstrates significant anti-tumor activity against human MM cell lines, regardless of their sensitivity to other therapeutic agents, against patient MM cells and is active in vivo using a MM xenograft mouse model. In contrast to the proline competitive PRS inhibitor halofuginone, NCP26 effects are not altered by exogenous proline levels. NCP26 treatment induces G0/G1 cell cycle arrest followed by apoptotic MM cell death, evidenced by depletion of mitochondrial membrane potential as well as caspase and PARP cleavage. Using combined transcriptomic and proteomic approaches we demonstrate a complex phenotypic response involving multiple pathways in protein quality control which center around the ribosome as integrating hub. Furthermore, we identified multiple proline rich motif containing protein targets of NCP26 as downstream effectors. These include myeloma survival factors such as syndecan 1 (SDC1, CD138), or basic helix-loop-helix transcription factors such as MYC, and transcription factor 3 (TCF3) suggesting that acute blockade of prolyl- aminoacylation evokes a complex pro-apoptotic response beyond the canonical amino acid starvation and integrated stress response. Taken together, our pre-clinical studies validate EPRS as a possible therapeutic target and provide the framework for evaluation of PRS inhibitors in a clinical setting.
2022-09-08 | GSE186447 | GEO
Project description:Inhibitor of prolyl-tRNA synthetase (PRS) to reduce tubulointerstitial nephritis
| PRJNA882069 | ENA
Project description:Aminoacyl tRNA synthetases (ARSs) are a class of enzymes with well-conserved housekeeping functions in cellular translation. Recent evidence suggests that ARS genes may participate in a wide array of cellular processes, and may contribute to the pathology of autoimmune disease, cancer, and other diseases. Several studies have suggested a role for the glutamyl prolyl tRNA synthetase (EPRS) in breast cancers, although none has demonstrated any underlying mechanism about how EPRS contributes to carcinogenesis. In this study, we identified EPRS as upregulated in estrogen receptor positive (ER+) human breast tumors in the TCGA and METABRIC cohorts, with copy number gains in nearly 50% of samples in both datasets. EPRS expression is associated with reduced overall survival in patients with ER+ tumors in TCGA and METABRIC datasets. EPRS expression was also associated with reduced distant relapse-free survival in patients treated with adjuvant tamoxifen monotherapy for five years, and EPRS-correlated genes were highly enriched for genes predictive of a poor response to tamoxifen. We demonstrated the necessity of EPRS for proliferation of tamoxifen-resistant ER+ breast cancer, but not ER- breast cancer cells. Transcriptomic profiling showed that EPRS regulated cell cycle and estrogen response genes. Finally, we constructed a causal gene network based on over 2500 ER+ breast tumor samples to build up an EPRS-estrogen signaling pathway. EPRS and its regulated estrogenic gene network may offer a promising alternative approach to target ER+ breast cancers that are refractory to current anti-estrogens.
2016-10-05 | GSE81162 | GEO
Project description:Purpose: In mammals, glutamyl-prolyl-tRNA synthetase (EPRS) catalyzes the attachment of two amino acids, glutamic acid (E) and proline (P), to their cognate tRNAs for protein synthesis. We aim to study the mechanism of EPRS in translational regulation of cardiac fibrosis and establish EPRS or its downstream target genes as potential anti-fibrosis therapeutic targets. The goals of this study are to use next generation sequencing (NGS)-derived fibroblast transcriptome profiling (RNA-seq) and translatome profiling (polysome-seq) followed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) methods to identify the downstream effector genes that are preferentially regulated by EPRS at the transcriptional and translational levels. Results: Using a well established data analysis workflow from the Genomic Research Center from University of Rochester Medical Center, we analyzed RNA-seq and polysome-seq data. We have identified novel Pro-rich (PRR) gene pathways that are preferentially regulated by EPRS via enhanced translation elongation at Pro-rich codons and antagonized by Halofuginone. Considering the translation active state in both light and heavy polysome fractions, we redefined the 4 groups by overlapping genes from heavy and light polysome associated transcripts compared to their total RNA expression change (p value <0.05 for differential expressed genes). 1371 genes were downregulated at translation (indicated by polysome-seq) and steady-state mRNA (indicated by RNA-seq) levels, and 775 genes were upregulated at both levels. There are a small number of genes whose gene regulation was changed in the opposite direction at the mRNA and translation levels. These observations indicate a coordinated regulatory effect between steady-state mRNA level and translation efficiency under the EPRS inhibitory condition. KEGG analysis of the genes that are reduced at RNA and translation levels revealed multiple pro-fibrotic pathways, including ECM-receptor interaction and proteoglycans. In contrast, the genes that are induced at RNA and translation levels are enriched in general translation factors, including ribosome and aminoacyl-tRNA biosynthesis, which suggests a compensatory amino acid starvation response upon EPRS inhibition. Altered expression of typical Pro-rich collagen and other genes was confirmed with qRT-PCR. Conclusions: Our study represents the first detailed analysis of fibroblast translatome in comparison with transcriptome under EPRS inhibitory condition (halofuginone treatment), with biological triplicates, generated by RNA-seq and polysome-seq technology. Our results show that the next generation sequencing offers a comprehensive qualitative and quantitative evaluation of mRNA content and its translation state within cells treated with translation inhibitory drug halofuginone (EPRS inhibitor). Based on our results, we conclude that Pro-rich motif bearing genes are preferential targets of EPRS, and mild inhibition of EPRS leads to inefficient translation of these PRR genes.
2021-09-09 | GSE136838 | GEO
Project description:Tubulointerstitial Transcriptome in the Neptune Cohort
2022-04-15 | GSE182380 | GEO
Project description:Transcriptome comparison of tubulointerstitial tissues from kidneys with focal segmental glomerulosclerosis (FSGS) and tubulointerstitial tissues from the unaffected portion of surgical nephrectomies. High-density Affymetrix Human Transcriptome Arrays (HTA) 2.0 were used for the gene expression analysis.
2019-01-29 | GSE125779 | GEO
Project description:Tubulointerstitial transcriptome from ERCB subjects with chronic kidney disease and living donor biopsies. Samples included in this analysis have been previously analyzed using older CDF definitions and are included under previous GEO submissions - GSE47184 (chronic kidney disease samples), and GSE32591 (IgA nephropathy samples). RNA from the tubulointerstitial compartment of was extracted and processed for hybridization on Affymetrix microarrays, annotated using Human Entrez Gene ID custom CDF version 19. This dataset is part of the TransQST collection.
2018-01-24 | E-GEOD-104954 | biostudies-arrayexpress
Project description:Pharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), PTC-LRP2 +/+ and -/- littermates in an LDL receptor -/- background were generated and fed a Western diet to determine effects of PTC-derived megalin on atherosclerosis. PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. By contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney. Overall, PTC-specific megalin deletion leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.
2024-07-04 | GSE268879 | GEO
Project description:Tubulointerstitial transcriptome data in the Neptune Cohort
| PRJNA550995 | ENA