Browse
Submit Data
Databases
API
Help

Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas

ABSTRACT: We used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that tumors from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments. p53+/â and p53+/âFbxw7+/â mice were generated by crossing p53-/- mice with Fbxw7+/- mice. At 5 weeks of age, mice were exposed whole-body to a single dose of 4 Gy X-ray irradiation. Mice were divided randomly into two groups and treated with rapamycin or placebo. RNA was isolated from thymic lymphomas.

ORGANISM(S): Mus musculus

SUBMITTER: Antoine Snijders

PROVIDER: E-GEOD-71975 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas

Project description:We used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that tumors from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments.

2015-10-31 | GSE71975 | GEO

mRNA-seq in DNA methylation deficient mouse embryonic fibroblasts

Project description:DNA methylation and the Polycomb Repression System are epigenetic mechanisms that play important roles in maintaining transcriptional repression. Recent evidence suggests that DNA methylation can attenuate the binding of Polycomb protein components to chromatin and thus plays a role in determining their genomic targeting. However, whether this role of DNA methylation is important in the context of transcriptional regulation is unclear. By genome-wide mapping of the Polycomb Repressive Complex 2 (PRC2)-signature histone mark, H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that hypomethylation leads to widespread H3K27me3 redistribution, in a manner that reflects the local DNA methylation status in wild-type cells. Unexpectedly, we observe striking loss of H3K27me3 and PRC2 from Polycomb-target gene promoters in DNA hypomethylated cells, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA hypomethylated cells, consistent with loss of Polycomb-mediated repression. An intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining PRC2 targeting. These observations identify a previously unappreciated role for DNA methylation in gene regulation and therefore influence our understanding of how this epigenetic mechanism contributes to normal development and disease. comparison of Dnmt1+/+ vs Dnmt1-/- mouse embryonic fibroblasts by strand-specific mRNA-seq

2013-03-01 | E-GEOD-44733 | biostudies-arrayexpress

mTOR kinase inhibition effectively decreases progression of a subset of neuroendocrine tumors that progress on rapalog therapy and delays cardiac impairment

Project description:Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNETs) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi) such as CC-223 could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors which progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared to placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long term cardioprotective benefit in those NET patients prone to carcinoid syndrome.

2017-10-16 | GSE102246 | GEO

Proteomic analysis of laser capture microdissected focal lesions in a rat model of progenitor marker-positive hepatocellular carcinoma

Project description:We have shown previously that rapamycin, the canonical inhibitor of the mechanistic target of rapamycin (mTOR) complex 1, markedly inhibits the growth of focal lesions in the resistant hepatocyte (Solt-Farber) model of hepatocellular carcinoma (HCC) in the rat. In the present study, we characterized the proteome of persistent, pre-neoplastic focal lesions in this model. One group was administered rapamycin by subcutaneous pellet for 3 weeks following partial hepatectomy and euthanized 4 weeks after the cessation of rapamycin. A second group received placebo pellets. Results were compared to unmanipulated control animals and to animals that underwent an incomplete Solt-Farber protocol to activate hepatic progenitor cells. Regions of formalin-fixed, paraffin-embedded tissue were obtained by laser capture microdissection (LCM). Proteomic analysis yielded 11,070 unique peptides representing 2,227 proteins. Quantitation of the peptides showed increased abundance of known HCC markers (e.g., glutathione S-transferase-P, epoxide hydrolase, 6 others) and potential markers (e.g., aflatoxin aldehyde reductase, glucose 6-phosphate dehydrogenase, 10 others) in foci from placebo-treated and rapamycin-treated rats. Peptides derived from cytochrome P450 enzymes were generally reduced. Comparisons of the rapamycin samples to normal liver and to the progenitor cell model indicated that rapamycin attenuated a loss of differentiation relative to placebo. We conclude that early administration of rapamycin in the Solt-Farber model not only inhibits the growth of pre-neoplastic foci but also attenuates the loss of differentiated function. In addition, we have demonstrated that the combination of LCM and mass spectrometry-based proteomics is an effective approach to characterize focal liver lesions.

2018-10-26 | PXD005845 | Pride

Transcription profiling of mouse Atm-/-,mTerc-/-,p53-/- triple knock-out lymphoma vs normal

Project description:Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the cancer process. Here, we engineered lymphoma-prone mice with chromosomal instability to assess the utility of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Integrating with targeted re-sequencing, our comparative oncogenomic studies efficiently identified FBXW7 and PTEN as commonly deleted or mutated tumor suppressors in human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). More generally, the murine cancers acquire widespread recurrent clonal amplifications and deletions targeting loci syntenic to alterations present in not only human T-ALL but also diverse tumors of hematopoietic, mesenchymal and epithelial types. These results thus support the view that murine and human tumors experience common biological processes driven by orthologous genetic events as they evolve towards a malignant phenotype. The highly concordant nature of genomic events encourages the use of genome unstable murine cancer models in the discovery of biologically relevant driver events in human cancer. Experiment Overall Design: 18 lymphoma samples from Atm-/-, mTerc-/-, p53-/- triple knock-out mice were analyzed. 3 week old hymus RNA from healthy mice of p53 Hets was used as reference. Each sample was hybridized with dye-swap replica.

2008-06-15 | E-GEOD-7607 | biostudies-arrayexpress

Expression data from c-Myc+ Notch1 T-ALL initiating cells

Project description:Missense FBXW7 mutations are prevalent in various tumors, including T-cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. We show here that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes, but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Three independent Notch1 T-ALL were derived on c-Myc-GFP background and sorted from the spleen of leukemic mice on the basis of GFP expression for RNA extraction and hybridization on Affymetrix microarrays

2013-05-10 | E-GEOD-46797 | biostudies-arrayexpress

Examination of hepatic SREBP-2 binding using ChIP-Seq

Project description:Sterol regulatory element binding proteins (SREBPs) are key transcriptional regulators of lipid metabolism. To define functional differences between the three mammalian SREBPs we are using genome-wide ChIP-seq with isoform-specific antibodies and chromatin from select tissues of mice challenged with different dietary conditions that enrich for specific SREBPs. We show hepatic SREBP-2 binds preferentially to two different gene-proximal motifs. Gene ontology analyses suggests SREBP-2 targets lipid metabolic processes as expected but apoptosis and autophagy gene categories were also enriched. We show SREBP-2 directly activates autophagy genes during cell sterol depletion, conditions known to induce both autophagy and nuclear SREBP-2 levels. Additionally, SREBP-2 knockdown during nutrient depletion decreased autophagosome formation and lipid droplet association of the autophagosome targeting protein LC3. Thus, the lipid droplet could be viewed as a third source of cellular cholesterol, which along with sterol synthesis and uptake, is also regulated by SREBP-2. Examination of hepatic SREBP-2 binding using ChIP-Seq. One ChIP-Seq dataset and one IgG control.

2011-03-22 | E-GEOD-28082 | biostudies-arrayexpress

Involvement of microRNA-related regulatory pathways in glucose-mediated control of Arabidopsis early seedling development

Project description:In plants, sugars such as glucose act as signaling molecules that promote changes in gene expression programs impacting on growth and development. Recent evidences have revealed the potential participation of mRNA decay control in some aspects of glucose-mediated regulatory responses suggesting a role of microRNAs (miRNAs) in these responses. In order to get a better understanding of glucose-mediated development modulation involving miRNA-related regulatory pathways, early seedling development of mutants impaired in miRNA biogenesis (hyl1-2) and miRNA-activity (ago1-25) were evaluated. Both mutants exhibited a glucose hyposensitive phenotype from germination up to seedling establishment, indicating that miRNA regulatory pathways may be involved in the glucose-mediated delay of early seedling development. The expression profile of 200 primary miRNA transcripts (pri-miRs) were evaluated by large-scale quantitative real-time polymerase chain reaction (qRT-PCR) profiling revealing that 38 pri-miRs were regulated by glucose. For several of them, the corresponding mature miRNAs are known to participate directly or indirectly in plant development, and their accumulation was shown to be co-regulated with the pri-miRNA by glucose. These data indicate that deficiency in miRNA machinery leads to a deregulated expression of several miRNA target genes in response to glucose. Also, such deficiencies result in glucose-promoted misexpression of genes for the three Abscisic Acid signaling elements ABI3, ABI4 and ABI5. Thus, miRNA-regulatory pathways play a role in the adjustments of growth and development triggered by glucose signaling. Three samples, including untreated control, 2% glucose-treated and 2% mannitol-treated samples.

2013-09-06 | E-GEOD-43546 | biostudies-arrayexpress

IDH1R132H activity in glioma cell lines and tumnor tissue (2HG)

Project description:We developed genetically engineered mice to generate brain tumors with especific genetic lessions. The animals were split in three groups: NRAS, P53 knockdown, IDH1-R132H and ATRX knock down (NPAID); NRAS, P53 knockdown, IDH1-R132H (NPI); NRAS, P53 knockdown, (NshP53). From these tumor we obtain and culture tumor cells growth like neurospheres and attached cells.

2015-03-05 | ST000312 | MetabolomicsWorkbench

Predicting drug response in human prostate cancer from preclinical analysis of in vivo mouse models (II)

Project description:Analysis of the transcriptome of allografted mouse tumors after treatment with rapamycin and PD0325901. Nkx3.1CreERT2/+; Ptenflox/flox; KrasLSL-G12D/+ (NPK mice) were induced and their tumors removed to generate allograft lines by implanting a 1.5 mm3 tumor fragment in the subcutaneous space of athymic nude mice. Allografted NPK tumors were allowed to grow until they reached a volume of 1 cm3, at which moment they were randomly assigned to either vehicle (Veh) or combination therapy using rapamycin and PD0325901 (RAPPD). Allografted mice were administered rapamycin (10 mg/kg) and PD0325901 (10 mg/kg) during five consecutive days (Allo SHORT). Mice were euthanized in the fifth day 6 hours after having received the last treatment and the tumors were harvested and snap frozen for subsequent molecular analysis.

2015-09-17 | GSE69213 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data