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SRP057629
Homo sapiens
10 Downloadable Samples
IlluminaHiSeq1500
Description
About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results. Overall design: A375p cells treated with10 µM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer''s instructions. Cells were previously treated with10 µM of either DEL22379, SCH772984 or DMSO as a control for two hours.
Publication Title
Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 31 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Integration Analysis of Three Omics Data Using Penalized Regression Methods: An Application to Bladder Cancer.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 31 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Omics data integration is becoming necessary to investigate the still unknown genomic mechanisms of complex diseases. During the integration process, many challenges arise such as data heterogeneity, the smaller number of individuals in comparison to the number of parameters, multicollinearity, and interpretation and validation of results due to their complexity and lack of knowledge about biological mechanisms. To overcome some of these issues, innovative statistical approaches are being developed. In this work, we applied penalized regression methods (LASSO and ENET) to explore relationships between common genetic variants, DNA methylation and gene expression measured in bladder tumor samples and have proposed a permutation-based method to concomitantly assess significance and correct by multiple testing with the MaxT algorithm. The overall analysis flow consisted of three steps: (1) SNPs/CpGs were selected per each gene probe within 1Mb window upstream and downstream the gene; (2) LASSO and ENET were applied to assess the association between each expression probe and the selected SNPs/CpGs in three multivariable models (SNP, CPG, and Global models, the latter integrating SNPs and CPGs); and (3) the significance of each model was assessed using the permutation-based MaxT method. We identified 48 genes whom expression levels were associated with both SNPs and GPGs. Importantly, we replicated results for 36 (75%) of them in an independent data set (TCGA). We checked the performance of the proposed method with a simulation study and further supported our results with a biological interpretation based on an enrichment analysis. The approach we propose allows reducing computational time and is flexibly and easy to implement when analyzing several omics data. Our results highlight the importance of integrating omics data by applying appropriate statistical strategies to discover new insights into the complexity of disease genetic mechanisms.
Publication Title
Integration Analysis of Three Omics Data Using Penalized Regression Methods: An Application to Bladder Cancer.
Sample Metadata Fields
Specimen part
View Samples- Drosophila melanogaster
- 16 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations
Publication Title
Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 68 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This series represents bone marrow aspirates from smoldering multiple myeloma patients
Publication Title
Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 48 Downloadable Samples
- NextSeq 500
Description
Liver X Receptors (LXRa and ß) are ligand-activated transcription factors that play a key role in the control of lipid homeostasis, as well as modulation of immunity and inflammation. Besides ligand binding, LXR activity can be regulated by posttranslational modifications, such as phosphorylation. This study aims to assess changes in bone marrow derived macrophage transcriptional profiles of mice that carry LysMcre directed phosphorylation deficient-version of LXRa compared (S196A) to wild-type (WT). Overall design: BMDM mRNA profiles of either LdlrKO or M-LXRa-S196A-LdlrKO male mice after being fed a Western diet for 12 weeks. 12 samples, 4 groups, in triplicate: (1) LdlrKO basal, (2) LdlrKO+ ligand, (3) M-LXRa-S196A-LdlrKO basal, (4) M-LXRa-S196A-LdlrKO+ligand
Publication Title
Disrupting LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 52 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarray analyses of patient myeloma cells (n=52) to correlate individual miRNA expression profiles with GEP-based risk defined by mRNA expression profilesx as well as clinical features of the disease. Unlike for mRNAs, genome-wide elevation of miRNA expression patterns were significantly positively associated with a mRNA-based GEP-risk score (P <.01) and proliferation index (P <.05). Consistent with our observation of global deregulation of miRNA expression profiles, silencing EIF2C2/AGO2, a gene component of the mRNA-based high-risk signature and a master regulator of the genesis and functionality of all miRNAs, dramatically decreased viability in myeloma cell lines.
Publication Title
High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Subject
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Translocations of ETS transcription factors are driver mutations in diverse cancers. We investigated the genomic network of the ETS fusion EWS/FLI1 in Ewing's sarcoma (ESFT) as a model of ETS-driven tumorigenesis. ChIP-Seq and transcriptional analysis identified E2F3 as a principle co-factor of EWSFLI1 defining functionally distinct gene sets. While EWS/FLI1 binding independent of E2F3 predominantly associated with repressed differentiation genes, significant co-localization with E2F3 was discovered at proximal promoters of activated growth-related genes. Thus, EWS/FLI1 promotes oncogenesis by simultaneously perturbing differentiation state and augmenting the expression of genes co-regulated by E2F3. Integration of additional E2F3 and ERG localization data from prostate cancer containing TMPRSS2/ERG verified that the ETS-E2F module is also found in prostate cancer and may be of general relevance to ETS driven cancers.
Publication Title
Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer.
Sample Metadata Fields
Disease, Cell line, Treatment, Time
View Samples- Mus musculus
- 24 Downloadable Samples
- NextSeq 500
Description
Liver X Receptors (LXRa and ß) are ligand-activated transcription factors that play a key role in the control of lipid homeostasis, as well as modulation of immunity and inflammation. LXR activity can be regulated by posttranslational modifications, such as phosphorylation. This study aims to assess changes in the hepatic transcriptional profiles of mice that carry a whole-body phosphorylation deficient knock in mutant of LXRa (S196A) compared to wild-type (WT) upon being fed a HFHC diet. Overall design: Liver mRNA profiles of either wild-type (WT) or LXRa-S196A female mice after being fed a High Fat-High Cholesterol diet for 6 weeks. Three biological replicate samples for each group are included. WT samples are used as controls.
Publication Title
Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease.
Sample Metadata Fields
Sex, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 24 Downloadable Samples
- NextSeq 500
Description
Liver X Receptors (LXRa and ß) are ligand-activated transcription factors that play a key role in the control of lipid homeostasis, as well as modulation of immunity and inflammation. LXR activity can be regulated by posttranslational modifications, such as phosphorylation. This study aims to assess changes in the hepatic transcriptional profiles of mice that carry a whole-body phosphorylation deficient knock in mutant of LXRa (S196A) compared to wild-type (WT) fed a chow diet. Overall design: Liver mRNA profiles of either wild-type (WT) or LXRa-S196A 16-week old female mice on a chow diet. Three biological replicate samples for each group are included. WT samples are used as controls.
Publication Title
Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples