Aneuploidy-induced cellular stresses limit autophagic degradation.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE60570 | GEO | 2015/10/26
SECONDARY ACCESSION(S): PRJNA258554
REPOSITORIES: GEO
Similar Datasets
Project description:An unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Determining how aneuploidy affects cells is thus critical to understanding tumorigenesis. Here we show that aneuploidy interferes with the degradation of autophagosomes within lysosomes. Mis-folded proteins that accumulate in aneuploid cells due to aneuploidy-induced proteomic changes overwhelm the lysosome with cargo, leading to the observed lysosomal degradation defects. Importantly, aneuploid cells respond to lysosomal saturation. They activate a lysosomal stress pathway that specifically increases the expression of genes needed for autophagy-mediated protein degradation. Our results reveal lysosomal saturation as a universal feature of the aneuploid state that must be overcome during tumorigenesis. RPE-1 cells either untreated or treated with one of Reversine, Bafilomycin A1 or MG132, each condition was done in triplicate. D14-*_Control: untreated control D14-*_Rev: cells treated with 0.5uM Reversine for 24hrs and harvested 48hrs later D14-*_Baf: cells treated with 0.1uM BafA1 for 6hrs D14-*_Mg: cells treated with 1uM MG132 for 24 hrs
2015-10-26 | E-GEOD-60570 | biostudies-arrayexpress
Project description:Aneuploidy causes a proliferative disadvantage in all normal cells analyzed to date, yet this condition is associated with a disease characterized by unabated proliferative potential, cancer. The mechanisms that allow cancer cells to tolerate the adverse effects of aneuploidy are not known. To probe this question, we identified aneuploid yeast strains with improved proliferative abilities. Their molecular characterization revealed strain-specific genetic alterations as well as mutations shared between different aneuploid strains. Among the latter, a loss-of-function mutation in the gene encoding the deubiquitinating enzyme Ubp6 improves growth rates in four different aneuploid yeast strains by attenuating the changes in intracellular protein composition caused by aneuploidy. Our results demonstrate the existence of aneuploidy-tolerating mutations that improve the fitness of multiple different aneuploidies and highlight the importance of ubiquitin-proteasomal degradation in suppressing the adverse effects of aneuploidy.
2010-02-25 | GSE20464 | GEO
Project description:Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a meta-analysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly-related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, while genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical anti-proliferative response that must be overcome prior to transformation. These experiments are two-color hybridizations of RNA isolated from aneuploid samples vs matched wt cells, all grown to midlog phase.
2012-06-28 | E-GEOD-35853 | biostudies-arrayexpress
Project description:Aneuploidy causes a proliferative disadvantage in all cells analyzed to date, yet this condition is associated with a disease characterized by unabated proliferative potential, cancer. The mechanisms that allow cancer cells to tolerate the adverse effects of aneuploidy are not known. To probe this question, we identified aneuploid yeast strains with high proliferative abilities and characterized their genetic alterations. We found both strain-specific genetic alterations and mutations shared between different aneuploid strains. One such mutation, a loss of function mutation in the gene encoding the deubiquitinating enzyme UBP6, improves growth rates in four different aneuploid yeast strains. Our data further suggest that deletion of UBP6 attenuates the effects of aneuploidy on cellular protein composition. Our results demonstrate the existence of aneuploidy-tolerating mutations that improve the fitness of multiple different aneuploidies and highlight the importance of ubiquitin-proteasomal degradation in suppressing the adverse effects of aneuploidy. This dataset contains both expression analysis and CGH of yeast strains bearing extra chromosomes. In all cases, the wt euploid strain grown under the same conditions was used as the reference sample. Reference nucleic acid was generally labeled with Cy3, though some were labeled with Cy5 as indicated in the associated annotations for each array. No replicate arrays are included. Expression Samples: GSM513249-GSM513277 CGH Samples: GSM513278-GSM513369
2010-02-24 | E-GEOD-20464 | biostudies-arrayexpress
Project description:Aneuploidy causes severe developmental defects and is a near universal feature of tumor cells. Despite its profound effects, the cellular processes affected by aneuploidy are not well characterized. Here, we examined the consequences of aneuploidy on the proteome of aneuploid budding yeast strains. We show that although protein levels largely scale with gene copy number, subunits of multi-protein complexes are notable exceptions. Posttranslational mechanisms attenuate their expression when their encoding genes are in excess. Our proteomic analyses further revealed a novel aneuploidy-associated protein expression signature characteristic of altered metabolism and redox homeostasis. Indeed aneuploid cells harbor increased levels of reactive oxygen species (ROS). Interestingly, increased protein turnover attenuates ROS levels and this novel aneuploidy-associated signature and improves the fitness of most aneuploid strains. Our results show that aneuploidy causes alterations in metabolism and redox homeostasis. Cells respond to these alterations through both transcriptional and posttranscriptional mechanisms.
2014-08-14 | PXD001019 | Pride
Project description:Aneuploidy, or an aberrant karyotype, results in developmental disabilities and has been implicated in tumorigenesis. However, the causes of aneuploidy-induced phenotypes and the consequences of aneuploidy on cell physiology remain poorly understood. We have performed a meta-analysis on gene expression data from aneuploid cells in diverse organisms, including yeast, plants, mice, and humans. We found highly-related gene expression patterns that are conserved between species: genes that were involved in the response to stress were consistently upregulated, while genes associated with the cell cycle and cell proliferation were downregulated in aneuploid cells. Within species, different aneuploidies induced similar changes in gene expression, independent of the specific chromosomal aberrations. Taken together, our results demonstrate that aneuploidies of different chromosomes and in different organisms impact similar cellular pathways and cause a stereotypical anti-proliferative response that must be overcome prior to transformation.
2012-06-29 | GSE35853 | GEO
Project description:Autophagy plays important roles in malignant pathogenesis and drug resistance. We used medicinal chemistry approaches to generate a series of novel agents that inhibit autophagic degradation. ROC-325 was selected as a lead compound for further evaluation. Comprehensive in vitro and in vivo studies were conducted to evaluate the selectivity, tolerability, and efficacy of ROC-325 in preclinical models of renal cell carcinoma (RCC). ROC-325 exhibited superior in vitro anticancer effects than the existing autophagy inhibitor hydroxychloroquine in 12 different tumor models with diverse genetic backgrounds. Focused studies of the mechanism of action and efficacy of ROC-325 in RCC cells showed that drug treatment induced hallmark characteristics of autophagy inhibition including accumulation of autophagosomes with undegraded cargo, lysosomal deacidification, p62 stabilization, and disruption of autophagic flux. Subsequent experiments showed that ROC-325 antagonized RCC growth and survival in an ATG5/7-dependent manner, induced apoptosis, and exhibited favorable selectivity. Oral administration of ROC-325 to mice bearing 786-0 RCC xenografts was well tolerated, significantly more effective at inhibiting tumor progression than HCQ, and inhibited autophagy in vivo. We used microarrays to determine gene expression changes following 24 h treatment with ROC-325 in RCC cell lines and identified differentially expressed genes.
2018-02-16 | GSE89766 | GEO
Project description:Background:Human aneuploidy is the leading cause of early pregnancy loss, mental retardation, and multiple congenital anomalies. Due to the high mortality associated with aneuploidy, the pathophysiological mechanisms of aneuploidy syndrome remain largely unknown. Previous studies focused mostly on whether dosage compensation occurs, and the next generation transcriptomics sequencing technology RNA-seq is expected to eventually uncover the mechanisms of gene expression regulation and the related pathological phenotypes in human aneuploidy. Results:Using next generation transcriptomics sequencing technology RNA-seq, we profiled the transcriptomes of four human aneuploid induced pluripotent stem cell (iPSC) lines generated from monosomy X (Turner syndrome), trisomy 8 (Warkany syndrome 2), trisomy 13 (Patau syndrome), and partial trisomy 11:22 (Emanuel syndrome) as well as two umbilical cord matrix iPSC lines as euploid controls to examine how phenotypic abnormalities develop with aberrant karyotype. A total of 466 M (50-bp) reads were obtained from the six iPSC lines, and over 13,000 mRNAs were identified by gene annotation. Global analysis of gene expression profiles and functional analysis of differentially expressed (DE) genes were implemented. Over 5000 DE genes are determined between aneuploidy and euploid iPSCs respectively while 9 KEGG pathways are overlapped enriched in four aneuploidy samples. Conclusions:Our results demonstrate that the extra or missing chromosome has extensive effects on the whole transcriptome. Functional analysis of differentially expressed genes reveals that the genes most affected in aneuploid individuals are related to central nervous system development and tumorigenesis. Four aneuploid iPSC (trisomy 8, trisomy 13, partial trisomy 11:22, monosomy X) and two euploid iPSC mRNA profiles were generated by deep sequencing, using SOLiD v3 platform. Gene expression values were compared.
2013-09-24 | E-GEOD-49247 | biostudies-arrayexpress
Project description:Aneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, whether and how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene expression patterns have been reported: an environmental stress response (ESR) and a “common aneuploidy gene-expression” (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate and bring clarity to this controversy. We show that the CAGE signature is not an aneuploidy-specific gene expression signature but is the result of euploid control cells, but not aneuploid cells, having grown into stationary phase. Because growth into stationary phase is amongst the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells are found to exhibit the ESR. We further show that the ESR causes a selective loss of ribosomes in aneuploid cells, providing an explanation for the decreased cellular density in aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than a CAGE signature, in response to aneuploidy-induced cellular stresses that results in selective ribosome loss.
2020-06-16 | GSE146791 | GEO
Project description:<p>Aneuploidy causes system-wide disruptions in the stochiometric balances of transcripts, proteins, and metabolites, often resulting in detrimental effects for the organism. The protozoan parasite Leishmania has an unusually high tolerance for aneuploidy, but the molecular and functional consequences for the pathogen remain poorly understood. Here, we addressed this question in vitro and present the first integrated analysis of the genome, transcriptome, proteome, and metabolome of highly aneuploid Leishmania donovani strains. Our analyses unambiguously establish that aneuploidy in Leishmania proportionally impacts the average transcript- and protein abundance levels of affected chromosomes, ultimately correlating with the degree of metabolic differences between strains. This proportionality was present in both proliferative and non-proliferative in vitro promastigotes. However, protein complex subunits and non-cytoplasmic proteins, showed dosage compensation, responding less or even not at all to aneuploidy-induced dosage changes. In contrast to other Eukaryotes, we did not observe the widespread regulation at the transcript level that typically modulates some of the negative effects of aneuploidy. Further, the majority of differentially expressed proteins between aneuploid strains were encoded by non-aneuploid chromosomes and were not driven by a significant underlying transcript change, suggesting that aneuploidy is accompanied by extensive post-transcriptional protein-level modulation. This makes Leishmania a unique Eukaryotic model for elucidating post-transcriptional protein-abundance modulation in the context of aneuploidy.</p><p><br></p><p><strong>Data availability:</strong></p><p>Proteomic data associated with this study are available in the PRIDE repository: accession number <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD028521' rel='noopener noreferrer' target='_blank'>PXD028521</a>.</p>
2022-09-19 | MTBLS1612 | MetaboLights