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GSE12694
Mus musculus
4 Downloadable Samples
Description
Glioblastoma (GBM) is a highly lethal brain tumor presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as high-grade disease that typically harbors EGFR, PTEN and Ink4a/Arf mutations, and the secondary GBM subtype evolves from the slow progression of low-grade disease that classically possesses PDGF and p53 events1. Here, we show that concomitant CNS-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with striking clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted p53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of p53 as well the expected PTEN mutations. Integrated transcriptomic profling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives elevated c-Myc levels and its associated signature. Functional studies validated increased c-Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of p53-Pten null NSCs as well as tumor neurospheres (TNSs) derived from this model. c-Myc also serves to maintain robust tumorigenic potential of p53-Pten null TNSs. These murine modeling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumor suppressor mutation profile in human primary GBM and establish c-Myc as a key target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.
Publication Title
p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 5 Downloadable Samples
Description
Almost all human pancreatic ductal adenocarcinomas (PDACs) are driven by oncogenic Kras and the progression of the disease is characterized by the serial appearance of certain genetic lesions. Mouse models have convincingly shown that Kras mutation induces classical PanIN lesions that can progress to PDAC in the appropriate tumor suppressor background. However, the cooperative mechanism between mutant Kras-dependent signaling surrogates and other oncogenic pathways remains to be fully elucidated in order to devise better therapeutic strategy. Mounting evidence PTEN/PI3K perturbation on PDAC tumorigenesis, we observed frequent PTEN inactivation at both genomic and histopathological levels in primary human PDAC samples. The importance of PTEN/PI3K pathway during the development of PDAC was further supported by genetic studies demonstrating that Pten deficiency in cooperation with Kras activation accelerated the formation of invasive PDAC. Mechanistically, combined Kras mutation and Pten inactivation leads to NFkB activation and subsequent induction of cytokine pathways, accompanied with strong stromal activation and immune cell infiltration. Therefore, PTEN/PI3K pathway dictates the activity of NFkB network and serves as a major surrogate during Kras-mediated pancreatic tumorigenesis.
Publication Title
PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 13 Downloadable Samples
Description
The maintenance of advanced malignancies relies on continued activity of driver oncogenes, although their rate-limiting role is highly context-dependent with respect to tumor types and associated genetic alterations. Oncogenic Kras mutation is the signature event in human pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven p53 mutant PDAC mouse model establishes that advanced PDAC remains strictly dependent on continued KrasG12D expression and that KrasG12D serves a vital role in the control of tumor metabolism, through stimulation of glucose uptake and channeling of glucose intermediates through the hexosamine biosynthesis pathway (HBP) and the pentose phosphate pathway (PPP). Notably, these studies reveal that oncogenic Kras regulates ribose biogenesis. Unlike canonical models of PPP-mediated ribose biogenesis, we demonstrate that oncogenic Kras drives intermediates from enhanced glycolytic flux into the non-oxidative arm of the PPP, thereby decoupling ribose biogenesis from NADPNADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in Kras-driven PDAC.
Publication Title
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 19 Downloadable Samples
Description
In this dataset, we include the expression data obtained from KRas expressing tumors, matched Kras expressing tumor spheres, surviving cells and surviving cells after KRas re-expression for 24hs
Publication Title
Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Sirt1 Regulates DNA Methylation and Differentiation Potential of Embryonic Stem Cells by Antagonizing Dnmt3l.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Stem-cells and transformed cancer cells specifically express a polycomb repressive complex subtype, PRC4 which characteristically contains Sirt1 (Sirtuin-1), a NAD+ dependent class III histone deacetylase (HDAC) and Eed2 isoform as specific members. Analyzing the transcriptiome and methylome analysis of Sirt1 deficient murine ESCs (Sirt1-/- ESC), we demonstrate that these cells repressed specifically on some genomic imprinted and germ-line related genes.
Publication Title
Sirt1 Regulates DNA Methylation and Differentiation Potential of Embryonic Stem Cells by Antagonizing Dnmt3l.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
Description
The genetic mechanism governing the spatial patterning of teeth still remains to be elucidated. Sonic hedgehog (Shh) is one of key signaling molecules involved in the spatial patterning of teeth. By utilizing maternal transfer of 5E1 (an IgG1 monoclonal antibody against Shh protein) through the placenta to block Shh signaling, we investigated the changes in tooth patterning and in gene expression.
Publication Title
Interactions between Shh, Sostdc1 and Wnt signaling and a new feedback loop for spatial patterning of the teeth.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Equine herpesvirus 1 (EHV-1) is the causative agent of a number of equine pathological states, including severe disease of the central nervous system, respiratory infections, and abortion storms. Our results showed that intranasal immunization with CpG-B oligodeoxynucleotides (ODN) protects CBA mice from lethal EHV-1 challenge. IFN-γ and seven interferon-stimulated genes (ISGs) were upregulated 39.4- to 260.3-fold at 8 h postchallenge in the lungs of RacL11-challenged mice that had been immunized with CpG-B ODN. Treatment with 20 ng/ml of IFN-γ reduced EHV-1 yield by 100-fold in MH-S at 4 days post-VZV infection compared to that of untreated cells. However, IFN-γ reduced virus yield by only 2-fold in and mouse fibroblast L-M cells. To identify IFN-γ-stimulated genes that inhibit EHV-1 replication, Affymetrix microarray analyses were performed with IFN-γ-treated MH-S and L-M cells. In MH-S cells, IFN-γ upregulated 551 genes and down-regulated 136 genes as compared to those of untreated cells. In L-M cells, IFN-γ upregulated 225 genes and downregulated 2 genes. Nine genes associated with innate immune response were significantly upregulated only in MH-S cells. Five antiviral ISGs MX1, SAMHD1, NAMPT, TREX1, and DDX60 were upregulated 3.2- to 18.1-fold only in MH-S cells. These results suggest that CpG-B ODN may be used as a prophylactic agent in horses.
Publication Title
Interferon Gamma Inhibits Equine Herpesvirus 1 Replication in a Cell Line-Dependent Manner.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
Description
In eukaryotes, regulation of mRNA translation enables a fast, localized and finely tuned expression of gene products. Within the translation process, the first stage of translation initiation is most rigorously modulated by the actions of eukaryotic initiation factors (eIFs) and their associated proteins. These 11 eIFs catalyze the joining of the tRNA, mRNA and rRNA into a functional translation complex. Their activity is influenced by a wide variety of extra- and intracellular signals, ranging from global, such as hormone signaling and unfolded proteins, to specific, such as single amino acid imbalance and iron deficiency. Their action is correspondingly comprehensive, in increasing or decreasing recruitment and translation of most cellular mRNAs, and specialized, in targeting translation of mRNAs with regulatory features such as a 5 terminal oligopyrimidine tract (TOP), upstream open reading frames (uORFs), or an internal ribosomal entry site (IRES). In mammals, two major pathways are linked to targeted mRNA translation. The target of rapamycin (TOR) kinase induces translation of TOP and perhaps other subsets of mRNAs, whereas a family of eIF2 kinases does so with mRNAs containing uORFs or an IRES. TOR targets translation of mRNAs that code for proteins involved in translation, an action compatible with its widely accepted role in regulating cellular growth. The four members of the eIF2 kinase family increase translation of mRNAs coding for stress response proteins such as transcription factors and chaperones. Though all four kinases act on one main substrate, eIF2, published literature demonstrates both common and unique effects by each kinase in response to its specific activating stress. This suggests that the activated eIF2 kinases regulate the translation of both a global and a specific set of mRNAs. Up to now, few studies have attempted to test such a hypothesis; none has been done in mammals.
Publication Title
eIF2alpha kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 2 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection.
Sample Metadata Fields
Specimen part
View Samples