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Alteration of gene expression profile in HEK293 cells treated with proteasome inhibitor epoxomicin

ABSTRACT: The objective of this study is to identify the genes that are up-regulated amid proteasome dysfunction to facilitate the discovery of proteolytic pathways that are activated as a compensatory response to proteasome inhibition. Proteasome is a large multi-component proteolytic complex in the cell. It is responsible for the constitutive turn-over of many cellular proteins as well as the degradation of oxidized and/or unfolded proteins. With such a fundamental role in the cell, disruption of proteasome understandably can lead to disastrous outcome. Oxidative stress has been postulated as the driving mechanism for aging. Oxidatively modified proteins, which usually have lost their activity, require immediate removal by proteasome to maintain normal cellular function. Dysfunction of proteasome has also been linked to neuro-degenerative diseases such as Alzheimer’s and Parkinson’s diseases, those that are most commonly seen in aged population. There is more than one proteolytic pathway in the cell, and it has been reported that obstruction of any one of these pathways may enhance the activity of the others. Proteasomal function has been found to have decreased during aging, prompting researchers to hypothesize that failure to remove oxidized proteins may play an important role in aging. It would be interesting to determine the other proteolytic pathways that are activated after proteasome inhibition by a relatively specific inhibitor epoxomicin to help understand their roles in aging processes. Keywords: time course, proteasome, inhibitor, oxidative stress, epoxomicin

ORGANISM(S): Homo sapiens

PROVIDER: GSE14429 | GEO | 2009/01/15

SECONDARY ACCESSION(S): PRJNA111757

REPOSITORIES: GEO

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Transcription profiling by array of human HEK293 cells treated with the proteasome inhibitor epoxomicin

Project description:The objective of this study is to identify the genes that are up-regulated amid proteasome dysfunction to facilitate the discovery of proteolytic pathways that are activated as a compensatory response to proteasome inhibition. Proteasome is a large multi-component proteolytic complex in the cell. It is responsible for the constitutive turn-over of many cellular proteins as well as the degradation of oxidized and/or unfolded proteins. With such a fundamental role in the cell, disruption of proteasome understandably can lead to disastrous outcome. Oxidative stress has been postulated as the driving mechanism for aging. Oxidatively modified proteins, which usually have lost their activity, require immediate removal by proteasome to maintain normal cellular function. Dysfunction of proteasome has also been linked to neuro-degenerative diseases such as Alzheimer?¢¬Ä¬ôs and Parkinson?¢¬Ä¬ôs diseases, those that are most commonly seen in aged population. There is more than one proteolytic pathway in the cell, and it has been reported that obstruction of any one of these pathways may enhance the activity of the others. Proteasomal function has been found to have decreased during aging, prompting researchers to hypothesize that failure to remove oxidized proteins may play an important role in aging. It would be interesting to determine the other proteolytic pathways that are activated after proteasome inhibition by a relatively specific inhibitor epoxomicin to help understand their roles in aging processes. Experiment Overall Design: Human embryonic kidney cells (HEK293) were untreated or treated with 1 uM epoxomicin for 1 and 6 hours. Total RNA was extracted for gene expression profiling using Affymetrix human genome U133 2.0 plus chip. A quadrupliate was prepared for each treatment. Experiment Overall Design: contributor: NHLBI Gene Expression Core Facility

2009-01-27 | E-GEOD-14429 | biostudies-arrayexpress

Modulation of protease expression by PITX transcription factors regulates protein quality control during aging

Project description:Protein quality control is important for healthy aging and is dysregulated in several age-related diseases. The autophagy-lysosome and ubiquitin-proteasome systems are key for proteostasis but it remains largely unknown whether other proteolytic systems maintain protein quality control during aging. Here, we find that the expression of proteolytic enzymes (proteases/peptidases) distinct from the autophagy-lysosome and ubiquitin-proteasome systems declines during skeletal muscle aging in Drosophila. Age-dependent downregulation of proteases undermines proteostasis, as demonstrated by the increase in detergent-insoluble poly-ubiquitinated proteins and pathogenic huntingtin-polyQ in response to protease RNAi. Transcriptomic analysis identifies Ptx1, homologous to human PITX1/2/3, as a transcriptional regulator of proteases. Specifically, RNAi for Ptx1 increases the expression of age-downregulated proteases and improves protein quality. Moreover, muscle-specific expression of Ptx1 RNAi extends lifespan. These findings indicate that protein quality control is ensured during aging by autophagy/proteasome-independent proteases that degrade misfolded and aggregation-prone proteins and by their transcriptional modulator Ptx1.

2022-08-15 | GSE156346 | GEO

Concordance of hydrogen peroxide-induced 8-oxoguanine patterns with two cancer mutation signatures of upper GI tract tumors

Project description:Oxidative DNA damage has been linked to cancer, aging, inflammation, and other pathological conditions. Although the chemical nature of the damaged bases is well understood, the precise distribution of oxidatively damaged DNA bases in the human genome is not known. Here we have used the recently developed circle-damage-sequencing method to map two types of oxidative DNA damage, oxidized guanines produced by hydrogen peroxide and oxidized thymines created by treatment of cells with potassium permanganate, at single base resolution. We show that oxidized guanines, chiefly 8-oxo-G, occur strictly dependent on the G/C sequence context and show a pronounced peak at transcription start sites (TSS). We determined the trinucleotide sequence pattern of guanine oxidation. This pattern shows high similarity to the cancer-associated single base substitution signatures SBS18 and SBS36. SBS36 is found in colorectal cancers that carry mutations in MUTYH, encoding a DNA repair enzyme that operates on 8-oxo-G mispairs. SBS18 is common in inflammation-associated upper GI tract tumors including esophageal and gastric adenocarcinomas. Oxidized thymines induced by permanganate occur with a distinct dinucleotide specificity, 5’T-A/C, and are depleted at the TSS. Collectively, our data provides a comprehensive analysis of two types of oxidized DNA bases in the human genome and suggests that two cancer mutational signatures, SBS18 and SBS36, are caused by reactive oxygen species.

2022-04-12 | GSE184820 | GEO

Oxidative modifications of urinary proteins increase kidney stone risk

Project description:Clinical and animal studies have demonstrated the increasing evidence of oxidative stress in kidney stone disease. Recent findings have shown that the interactions between calcium oxalate (CaOx) crystals and renal tubular cells can promote many cellular events such as cell proliferation, cell death, cellular injury, mitochondrial dysfunction and inflammatory cascade. All of these cellular events are associated with oxidative stress and overproduction of free radicals and reactive oxygen species (ROS) such as superoxide and hydrogen peroxide in renal tubular cells. However, almost all of these references have shown that oxidative stress occurs after the causative crystals have been deposited in the kidney or exposed to renal tubular cells, whereas its primary role as the etiology remained unclear. In this study, we examined effects of oxidative modifications of urinary proteins on CaOx stone formation processes. Urinary proteins were modified by performic oxidation and the presence of oxidatively modified urinary proteins was verified, quantified and characterized by Oxyblot assay and tandem mass spectrometry (nanoLC-ESI-LTQ-Orbitrap-MS/MS). Subsequently, activities of oxidatively modified urinary proteins on CaOx stone formation processes were examined.

2021-11-03 | PXD019360 | Pride

Polarized Desmosome and Hemidesmosome Shedding via Exosomes is an Early Indicator of Outer Blood-Retina Barrier Dysfunction

Project description:The retinal pigmented epithelium (RPE) makes up the outer blood-retinal barrier, supports photoreceptor function of the eye and is constantly damaged by oxidative stress. Dysfunction of the RPE underlies pathology leading to development of age-related macular degeneration (AMD), the leading cause of vision loss among the elderly in industrialized nations. A major function of the RPE is to process photoreceptor outer segments which relies on the proper functioning of the RPE endocytic pathways and endosomal trafficking. RPE-released exosomes and other extracellular vesicles are essential parts of these pathways and may be early indicators of cellular stress. To test this, we used a polarized primary RPE cell culture model under chronic subtoxic oxidative stress to study the role of exosomes in the extracellular matrix (ECM) changes that underlie the early and late stages of AMD. Resulting unbiased proteomic analyses of highly purified basolateral exosomes from oxidatively stressed RPE cultures revealed changes to proteins involved in epithelial barrier integrity, that were detectable prior to overt cellular dysfunction. There were also changes to proteins accumulating in the basal-side sub-RPE ECM during oxidative stress, that could be prevented in the presence of an inhibitor of exosome release. We show for the first time that chronic subtoxic oxidative stress in primary RPE cultures induces proteomic changes in exosomes including basal-side specific desmosome and hemidesmosome shedding via exosomes. We also show that release of these exosomes correlates with ECM changes that can be partially prevented by inhibition of exosome release. These findings open a completely novel avenue for therapeutic intervention and access to early biomarkers of cellular dysfunction in aging-related retinal diseases, in particular AMD, and broadly from blood-CNS barriers in other neurodegenerative diseases.

2023-07-07 | MSV000092372 | MassIVE

The 19S proteasome regulates subtelomere silencing and facultative heterochromatin formation

Project description:The non-proteolytic role of the proteasome in heterochromatin regulation

2019-06-16 | GSE103336 | GEO

The 19S proteasome subunit Rpt4 is directly involved in the regulation of heterochromatin spreading

Project description:The non-proteolytic role of the proteasome in heterochromatin regulation

2018-02-16 | GSE97865 | GEO

Mitochondrial dysfunction induces oxidative stress and an impaired ubiquitin proteasome system to trigger the pathogenesis of Frontal Fibrosing Alopecia (FFA)

Project description:Mitochondrial dysfunction is implicated in myriad diseases. However, there is no single platform that facilitates mapping of mitochondrial pathways and processes essential for health and those that are defective in disease. Here, we manually curated 1008 mitochondrial proteins to create a database of 31 mitochondrial pathways and processes and named the database as ‘MitoGyan’. ‘Gyan’ in Sanskrit means knowledge. We also developed a mitochondria associated metabolic pathways visualization tool called MitoCyc within HumanCyc. Using these novel resources and an integrated ‘Omics’ approach, we demonstrate that mitochondrial dysfunction occurs early in a rare, inflammatory hair disease called Frontal Fibrosing Alopecia (FFA). Transmission electron microscopy and mass spectrometry show morphological and functional changes in the mitochondria of FFA hair follicles. Our data suggests that mitochondrial dysfunction induces oxidative stress and an impairment of the ubiquitin proteasome system (UPS) in FFA. We propose that mitochondria-targeted antioxidants provide a new therapeutic strategy for FFA. Microarray analyses of FFA was undertaken to decipher pathophysiological pathways of FFA leading to disease intitiation and progression

2021-12-21 | GSE58934 | GEO

Bulk mRNA sequencing of wildtype (WT) and mutator mouse embryonic fibroblasts (MEFs)

Project description:The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Inhibition of the respiratory chain impairs proteasome activity, regulation of proteasome function by mitochondrial metabolism, however, is unknown. Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome. Defects in respiratory chain caused metabolic reprogramming of the Krebs cycle and deficiency in the amino acid aspartate resulting in reduced 26S proteasome function. Aspartate supplementation fully restored assembly and activity of 26S proteasome complexes. This metabolic reprogramming involved sensing of aspartate via the mTORC1 pathway and the mTORC1-dependent transcriptional activation of defined proteasome assembly factors. Metabolic regulation of 26S function was confirmed in patient-derived skin fibroblasts with respiratory dysfunction containing a single mitochondrial mutation. Importantly, treatment of primary human lung fibroblasts with the respiratory chain inhibitor and anti-diabetic drug metformin similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Of note, reduced 26S activity conferred increased resistance towards the proteasome inhibitor Bortezomib, which was reversible upon pyruvate supplementation. Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications.

2020-07-26 | GSE153983 | GEO

A deeply conserved protease, acylamino acid-releasing enzyme (AARE), acts in aging in Physcomitrella and Arabidopsis

Project description:Protein oxidation results from the reaction of amino-acid side chains with reactive oxygen species (ROS) and is mostly irreversible. In non-photosynthetic tissues, mitochondria are a main source of ROS, whereas plastids are the major source in photosynthetic tissues. Oxidized proteins suffer from decreased structural integrity and even loss of function, and their accumulation ultimately leads to cytotoxic aggregates. In mammals, this correlates with aging and is linked to several age-related pathologies. Mammalian proteolytic pathways for clearance of oxidized proteins are under intensive research, while mechanistic insights into this process in plants is scarce. AARE enzymes are ATP-independent serine proteases presumably acting on oxidized proteins and operating in a dual exo-/endopeptidase mode. They are found in all domains of life. Here, we investigated AARE enzymes in the moss Physcomitrella and the angiosperm Arabidopsis and identified three homologous nuclear genes in Physcomitrella (PpAARE1-3) and a single nuclear gene in Arabidopsis (AtAARE). Surprisingly, we observed triple localization of the proteins AtAARE and PpAARE1 to plastids, mitochondria and the cytosol in vivo, likely conserved across the plant lineage. This represents an ATP-independent possibility for degradation of oxidized proteins in the major source organelles of ROS in plants, which is distinct to mammals. Combinatorial knockout plants and protein interaction analysis revealed specific interactions of the moss AARE isoforms and functions in progressive aging. Analysis of an AtAARE T-DNA mutant further suggests conservation of AARE function in age-related development.

2023-03-11 | PXD033854 | Pride

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