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SRP119838
Homo sapiens
24 Downloadable Samples
NextSeq 500
Description
BRAF oncogene is mutated in ~50% of human cutaneous melanomas. The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway fuelling cancer growth. The inhibitors of BRAF V600E (BRAFi), lead to massive and high response rate. However, BRAFi-resistant cells that operate as a cellular reservoir for relapses severely limits the duration of the clinical response. The recent depiction of these resistant cells did not identify druggable targets to ensure long-term survival under BRAFi. Here, we identify the aryl hydrocarbon receptor (AhR) as a target to eradicate resistant cells. We show that BRAFi bind to AhR on a new site, named beta-pocket, and reprogram gene expression independently of its partner ARNT. beta-pocket activation induces a pigmentation signature, which is associated to BRAFi-induced cell death of sensitive BRAF V600E melanoma cells and tumour shrinkage. Intriguingly, in resistant cells, BRAFi does not induced a pigmentation signature since these cells display another AhR program; AhR-ARNT dependant. By this way, AhR directs several key BRAFi-resistant genes. At single cell level, this constitutive activation of AhR-ARNT is identified in rare cells before BRAFi-treatment of melanoma tumours and an enrichment of these alpha-cells is observed under BRAFi. Our data strongly suggest that an endogenous AhR ligand activates AhR-ARNT via the canonical AhR pocket (alpha-pocket), thus favouring BRAFi-resistant gene expression. Importantly, we identify the clinically compatible AhR antagonist, the resveratrol (RSV), able to abrogate the deleterious constitutive activation of AhR and to reduce the cellular reservoir for the relapse. Taken together, this work reveals that constitutive AhR signalling drives BRAFi resistance and constitutes a therapeutic target to achieve long-term patient survival under BRAFi. More broadly, the constitutive activation of AhR by endogenous ligands is in line with the ability of UV radiations to generate potent AhR ligands and to favour melanoma onset. Overall design: Total RNA isolated from 12 human melanoma cell lines (501Mel) after different treatments was subjected to multiplexed RNA-sequencing using Illumina NextSeq500 sequencing tehnology.
Publication Title
Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Triticum turgidum subsp. durum, Triticum aestivum
- 17 Downloadable Samples
Affymetrix Wheat Genome Array (wheat)
Description
To provide a global study of transcriptome changes under drought stress, the gene expression levels of a durum wheat genotype (Triticum durum Desf. cultivar Creso) and two bread wheat genotypes (Triticum aestivum L. cultivar Chinese Spring -CS- and its deletion line CS_5AL-10) were investigated. The 5A chromosome deletion line (5AL-10) lacks the distal part (43%) of the long arm of chromosome 5A. Each genotype was subjected to two different levels of water stress at the grain filling stage. After anthesis, three different levels of soil water content (SWC) were induced as described below: control (CTRL; SWC=28%), moderate stress (MS; SWC=18%), and severe stress (SS; SWC=12.5%). For each sample, three biological replicates were performed, for a total of 27 hybridizations. ****[PLEXdb(http://www.plexdb.org) has submitted this series at GEO on behalf of the original contributor, Alessio Aprile. The equivalent experiment is TA23 at PLEXdb.]
Publication Title
Transcriptional profiling in response to terminal drought stress reveals differential responses along the wheat genome.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the PAX3-FOXO1 fusion gene. Despite its discovery over almost 20 years ago, PAX3-FOXO1 remains an enigmatic tumor driver. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence. Here, we show that bypass occurs in part by PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member, which then suppresses the evolutionarily conserved mammalian Hippo/Mst1 pathway. RASSF4 loss-of-function activates Hippo/Mst1 and inhibits downstream YAP, causing aRMS cell cycle arrest and senescence. This is the first evidence for an oncogenic role for RASSF4, and a novel mechanism for Hippo signaling suppression in human cancer.
Publication Title
Alveolar rhabdomyosarcoma-associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Affymetrix microarrays were used to determine the mRNA composition of mRNPs obtained by immunoprecipitation with IRP1 (iron regulatory protein 1).
Publication Title
Identification of target mRNAs of regulatory RNA-binding proteins using mRNP immunopurification and microarrays.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Shiga toxins (Stxs) are bacterial cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli that cause bacillary dysentery and hemorrhagic colitis, respectively. To date, approaches to studying the capacity of Stxs to alter gene expression in intoxicated cells have been limited to individual genes. However, it is known that many of the signaling pathways activated by Stxs regulate the expression of multiple genes in mammalian cells. To expand the scope of analysis of gene expression and to better understand the underlying mechanisms for the various effects of Stxs on cell functions, we carried out comparative microarray analyses to characterize the global transcriptional response of human macrophage-like THP-1 cells to Shiga toxin type 1 (Stx1) and LPS. Data were analyzed using a rigorous combinatorial approach with three separate statistical algorithms. Thirty-six genes met the criteria of up-regulated expression in response to Stx1 treatment with 14 genes uniquely up-regulated by Stx1. Microarray data were validated by real time RT-PCR for genes encoding Egr-1 (transcriptional regulator), COX-2 (inflammation), and DUSP1, 5 and 10 (regulation of MAPK signaling). Stx1-mediated signaling through ERK1/2 and Egr-1 appears to be involved in the increased expression of the proinflammatory mediator TNF-. Activation of COX-2 expression is associated with the increased production of proinflammatory and vasoactive eicosanoids. However, the capacity of Stx1 to increase the expression of genes encoding phosphatases suggests that mechanisms to dampen the macrophage proinflammatory response may be built into host response to the toxins.
Publication Title
Global transcriptional response of macrophage-like THP-1 cells to Shiga toxin type 1.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Mesothelia, which cover all coelomic organs and body cavities in vertebrates, perform diverse functions in embryonic and adult life. Yet, mesothelia are traditionally viewed as simple, uniform epithelia.
Publication Title
Autotaxin signaling governs phenotypic heterogeneity in visceral and parietal mesothelia.
Sample Metadata Fields
Specimen part
View Samples- Saccharomyces cerevisiae
- 70 Downloadable Samples
- Affymetrix Yeast Genome S98 Array (ygs98)
Description
We construced combinations of genetic deletions to infer genetic interactions in genomic expression data.
Publication Title
Prediction of phenotype and gene expression for combinations of mutations.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 44 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Swiss-Webster female mice (Charles River Laboratories, Wilmington, MA) 5-6 weeks of age were infected intranasally with 5 LD50 of either WT or lpp mutant of Y. pestis CO92. Uninfected mice were used as controls. At either 12 or 48 h post infection (p.i.), 3 mice per group were euthanized and the lungs, livers, and spleens were harvested and homogenized in 1 ml of RNALater (Ambion/Applied Biosystems, Austin, TX) using 50-ml tissue homogenizers (Kendell, Mansfield, MA). RNA was isolated from the tissue homogenates and purified using RNAqueous (Ambion). After an overnight precipitation, the RNA was resuspended in 20 ul of diethylpyrocarbonate (DEPC)-treated water and hybridized to Affymetrix GeneChip Mouse Genome 430 2.0 arrays, performed by the Molecular Genomics Core at UTMB Galveston, Texas, per manufacture protocols. The arrays had 45,000 probe sets representing more than 39,000 transcripts derived from ~34,000 well-substantiated mouse genes. The experiments were performed in triplicate (biological replicates), generating a total of 45 arrays.
Publication Title
Comparative Analyses of Transcriptional Profiles in Mouse Organs Using a Pneumonic Plague Model after Infection with Wild-Type Yersinia pestis CO92 and Its Braun Lipoprotein Mutant.
Sample Metadata Fields
Sex, Specimen part, Time
View Samples- Mus musculus
- 20 Downloadable Samples
- Illumina MouseRef-8 v2.0 expression beadchip
Description
Background: Epithelial-to-Mesenchymal Transition (EMT) is predicted to play a critical role in tumor progression and metastasis in Hepatocellular Carcinoma. Our goal was to elucidate a mechanism of tumor proliferation and metastasis using a novel murine model of EMT.
Publication Title
Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion.
Sample Metadata Fields
Specimen part
View Samples- Arabidopsis thaliana
- 12 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
In order to elucidate transcriptional and metabolic networks associated with Lys metabolism, we utilized developing seeds as a system in which Lys synthesis could be stimulated developmentally without application of chemicals and coupled this to a T-DNA insertion knockout mutation impaired in Lys catabolism. This seed-specific metabolic perturbation stimulated Lys accumulation starting from the initiation of storage reserve accumulation. Our results revealed that the response of seed metabolism to the inducible alteration of Lys metabolism was relatively minor, however, that which was observable operated in a modular manner. They also demonstrated that Lys metabolism is strongly associated with the operation of the TCA cycle, whilst largely disconnected from other metabolic networks. In contrast, the inducible alteration of Lys metabolism was strongly associated with gene networks, stimulating the expression of hundreds of genes controlling anabolic processes that are associated with plant performance and vigor, whilst suppressing a small number of genes associated with plant stress interactions. The most pronounced effect of the developmentally-inducible alteration of Lys metabolism was an induction of expression of a large set of genes encoding ribosomal proteins as well as genes encoding translation initiation and elongation factors, all of which are associated with protein synthesis. With respect to metabolic regulation, the inducible alteration of Lys metabolism was primarily associated with altered expression of genes belonging to networks of amino acids and sugar metabolism. The combined data are discussed within the context of network interactions both between and within metabolic and transcriptional control systems.
Publication Title
Deciphering transcriptional and metabolic networks associated with lysine metabolism during Arabidopsis seed development.
Sample Metadata Fields
No sample metadata fields
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