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GSE42762
Homo sapiens
9 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma.
Publication Title
FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Saccharomyces cerevisiae
- 8 Downloadable Samples
- Affymetrix Yeast Genome S98 Array (ygs98)
Description
Metabolic fluxes may be regulated "hierarchically," e.g., by changes of gene expression that adjust enzyme capacities (V(max)) and/or "metabolically" by interactions of enzymes with substrates, products, or allosteric effectors. In the present study, a method is developed to dissect the hierarchical regulation into contributions by transcription, translation, protein degradation, and posttranslational modification. The method was applied to the regulation of fluxes through individual glycolytic enzymes when the yeast Saccharomyces cerevisiae was confronted with the absence of oxygen and the presence of benzoic acid depleting its ATP. Metabolic regulation largely contributed to the approximately 10-fold change in flux through the glycolytic enzymes. This contribution varied from 50 to 80%, depending on the glycolytic step and the cultivation condition tested. Within the 50-20% hierarchical regulation of fluxes, transcription played a minor role, whereas regulation of protein synthesis or degradation was the most important. These also contributed to 75-100% of the regulation of protein levels.
Publication Title
The fluxes through glycolytic enzymes in Saccharomyces cerevisiae are predominantly regulated at posttranscriptional levels.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
More than two thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER- breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genome-wide approaches we have addressed the mechanism by which ER antagonizes the pro-apoptotic function of p53. Interestingly both ER agonists such as estradiol and selective ER modulators (SERM) such as tamoxifen promote p53 antagonism. In contrast the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This suggests an improved strategy for the treatment of ER+ breast cancer utilizing antagonists that completely block ER action together with drugs that activate p53-mediated cell death.
Publication Title
Estrogen receptor prevents p53-dependent apoptosis in breast cancer.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 146 Downloadable Samples
Affymetrix Human Transcriptome Array 2.0 (hta20), Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 146 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
Intra-tumor heterogeneity is a hallmark of glioblastoma multiforme, and thought to negatively affect treatment efficacy. Here we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability between clones, including a wide range of responses to radiation and drugs. This widespread variability was observed as a continuum of multitherapy resistance phenotypes linked to a proneural-to-mesenchymal shift in the transcriptome.
Publication Title
Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics.
Publication Title
Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 16 Downloadable Samples
Illumina Genome Analyzer, Illumina HiSeq 2000
Description
Estrogen has vascular protective effects in premenopausal women and in women under 60 receiving hormone replacement therapy. However, estrogen also increases risks of breast and uterine cancers and of venous thromboses linked to upregulation of coagulation factors in the liver. In mouse models, the vasoprotective effects of estrogen are mediated by the estrogen receptor alpha (ERa) transcription factor. Here, through next generation sequencing approaches, we show that almost all of the genes regulated by 17-b-estradiol (E2) differ between mouse aorta and mouse liver, and that this is associated with a distinct genomewide distribution of ERa on chromatin. Bioinformatic analysis of E2-regulated promoters and ERa binding site sequences identify several transcription factors that may determine the tissue specificity of ERa binding and E2-regulated genes, including the enrichment of NFkB, AML1 and AP-1 sites in the promoters of E2 downregulated inflammatory genes in aorta but not liver. The possible vascular-specific functions of these factors suggests ways in which the protective effects of estrogen could be promoted in the vasculature without incurring negative effects in other tissues. Our results also highlight the likely importance of rapid signaling of membrane-associated ERa to cellular kinases (altering the activities of transcription factors other than ER itself) in determining tissue specific transcriptional responses to estrogen. Overall design: The aortas or liver fragments of wild-type C57/BL6 mice were incubated ex vivo with 10nM E2 or ethanol vehicle for 4 hours before harvesting for RNA collection. Each condition was performed with two biological replicates, and each replicate contained aortas or liver fragments from 4 mice.
Publication Title
Research resource: Aorta- and liver-specific ERα-binding patterns and gene regulation by estrogen.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 86 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
mRNA profiles of thousands of human tumors are available, but methods to deduce oncogenic signaling networks from these data lag behind. It is especially challenging to identify main-regulatory routes, and to generalize conclusions obtained from experimental models. We designed the bioinformatic platform R2 in parallel with a wet-lab approach of neuroblastoma. Here we demonstrate how R2 facilitates an integrated analysis of our neuroblastoma data. Analysis of the MYCN pathway suggested important regulatory connections to the polyamine synthesis route, the Notch pathway and the BMP/TGF pathway. A network of genes emerged connecting major oncogenes in neuroblastoma. Genes in the network carried strong prognostic values and were essential for tumor cell survival.
Publication Title
Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 27 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Spinal cord injury leads to impaired motor and sensory functions. After spinal cord injury there is a an initial phase of hypo-reflexia followed by a developing hyper-reflexia, often termed spasticity. Previous studies have suggested a relationship between the reappearence of plateau potentials in motor neurons and the development of spasticity after spinalization. To understand the molecular mechanism behind this phenomenon we examined the transcriptional response of the motor neurons after spinal cord injury.
Publication Title
Global gene expression analysis of rodent motor neurons following spinal cord injury associates molecular mechanisms with development of postinjury spasticity.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Polo-Like Kinase 3 Appears Dispensable for Normal Retinal Development Despite Robust Embryonic Expression.
Sample Metadata Fields
Specimen part
View Samples