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GSE48363
Mus musculus
6 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Existing data suggest that NF-kappaB signaling is a key regulator of cancer-induced skeletal muscle wasting. However, identification of the components of this signaling pathway and of the NF-B transcription factors that regulate wasting is far from complete. In muscles of C26 tumor bearing mice, overexpression of d.n. IKK blocked muscle wasting by 69%, the IB-super repressor blocked wasting by 41%. In contrast, overexpression of d.n. IKK or d.n. NIK did not block C26-induced wasting. Surprisingly, overexpression of d.n. p65 or d.n. c-Rel did not significantly block muscle wasting. Genome-wide mRNA expression arrays showed upregulation of many genes previously implicated in muscle atrophy. To test if these upregulated genes were direct targets of NF-B transcription factors, we compared genome-wide p65 or p50 binding to DNA in control and cachectic muscle using ChIP-sequencing. Bioinformatic analysis of ChIP-seq data from control and C26 muscles showed increased p65 and p50 binding to a few regulatory and structural genes but only two of these genes were upregulated with atrophy. The p65 and p50 ChIP-seq data are consistent with our finding of no significant change in protein binding to an NF-B oligo in a gel shift assay. Taken together, these data support the idea that although inhibition of IB, and particularly IKK, blocks cancer-induced wasting, the alternative NF-B signaling pathway is not required. In addition, the downstream NF-B transcription factors do not regulate the transcriptional changes. These data are consistent with the growing body of literature showing that there are NF-B-independent substrates of IKK and IB that regulate physiological processes.
Publication Title
C26 cancer-induced muscle wasting is IKKβ-dependent and NF-kappaB-independent.
Sample Metadata Fields
Sex, Disease
View Samples- Mus musculus
- 48 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The glycopeptide antibiotic vancomycin (VCM) represents one of the last lines of defense against methicillin-resistant Staphylococcus aureus infections. However, vancomycin is nephrotoxic, but the mechanism of toxicity is still unclear.
Publication Title
Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarrays to detail the global programme of gene expression after knockdown of Ecdysoneless in hMECs
Publication Title
The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Breast cancers with HER2 overexpression are sensitive to drugs targeting the receptor or its kinase activity. HER2-targeting drugs are initially effective against HER2- positive breast cancer, but resistance inevitably occurs. We previously found that nuclear factor kappa B is hyper-activated in the subset of HER-2 positive breast cancer cells and tissue specimens. In this study, we report that constitutively active NF-B rendered HER2-positive cancer cells resistant to anti-HER2 drugs, and cells selected for Lapatinib resistance up-regulated NF-B. In both circumstances, cells were anti-apoptotic and grew rapidly as xenografts. Lapatinib-resistant cells were refractory to HER2 and NF-B inhibitors alone but were sensitive to their combination, suggesting a novel therapeutic strategy. A subset of NF-B-responsive genes was overexpressed in HER2-positive and triple-negative breast cancers, and patients with this NF-B signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-B activation, and selection for resistance results in NF-B activation, suggesting this transcription factor is central to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-B suggests a potential treatment paradigm for patients who relapse after anti-HER2 therapy. Patients with these cancers may be treated by simultaneously suppressing HER2 signaling and NF-B activation.
Publication Title
NF-κB activation-induced anti-apoptosis renders HER2-positive cells drug resistant and accelerates tumor growth.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Primary T cell activation involves the integration of three distinct signals delivered in sequence: 1) antigen recognition, 2) costimulation, and 3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing bystander T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4+ T cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted nave CD4+ but not CD8+ T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4+ T cell activation affecting memory generation, induction of autoimmunity, as well as impaired viral clearance. These data highlight the critical regulation of nave CD4+ T cells during inflammatory conditions.
Publication Title
Out-of-Sequence Signal 3 Paralyzes Primary CD4(+) T-Cell-Dependent Immunity.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 1 Downloadable Sample
- Illumina MouseWG-6 v2.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
S-adenosylmethionine levels regulate the schwann cell DNA methylome.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 22 Downloadable Samples
- Illumina MouseRef-8 v2.0 expression beadchip
Description
In this study we have analyzed the global gene expression of nave mouse embryonic stem cells in different culture conditions including R2i (PD0325901+SB431542), 2i (PD0325901+CHIR99021), and also PD0325901+LIF and SB431542+LIF to show the similarities and differences between the conditions in maintaining pluripotency.
Publication Title
Inhibition of TGFβ signaling promotes ground state pluripotency.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 1 Downloadable Sample
- Illumina MouseWG-6 v2.0 expression beadchip
Description
DNA methylation is a key epigenetic regulator of mammalian embryogenesis and somatic cell differentiation. Using high-resolution genome-scale maps of methylation patterns, we show that the formation of myelin in the peripheral nervous system, proceeds with progressive DNA demethylation, which coincides with an upregulation of critical genes of the myelination process. More importantly, we found that, in addition to expression of DNA methyltransferases and demethylases, the levels of S-adenosylmethionine (SAMe), the principal biological methyl donor, could also play a critical role in regulating DNA methylation during myelination and in the pathogenesis of diabetic neuropathy. In summary, this study provides compelling evidence that SAMe levels need to be tightly controlled to prevent aberrant DNA methylation patterns, and together with recently published studies on the influence of SAMe on histone methylation in cancer and embryonic stem cell differentiation show that in diverse biological processes, the methylome, and consequently gene expression patterns, are critically dependent on levels of SAMe.
Publication Title
S-adenosylmethionine levels regulate the schwann cell DNA methylome.
Sample Metadata Fields
No sample metadata fields
View Samples- Drosophila melanogaster
- 16 Downloadable Samples
Illumina Genome Analyzer IIx
Description
Transposable elements are a serious threat for genome integrity and their control via small RNA mediated silencing pathways is an ancient strategy. The fruit fly Drosophila melanogaster has two silencing mechanisms that repress TEs expression: endogenous siRNAs (esiRNAs or endo-siRNAs) and Piwi-interacting small RNAs (piRNAs). The biogenesis of endo-siRNAs involves Loqs-PD, which acts predominantly during processing of dsRNA by Dcr-2, and R2D2 that primarily helps to direct siRNAs for loading into Ago2. We provide deep sequencing evidence consistent with the idea that R2D2 and Loqs-PD can function in part redundantly. Certain transposons display a preference for either dsRBD-protein for production or loading; this appeared to correlate neither with overall abundance, classification of the transposon or a specific site of genomic origin. The endo-siRNA biogenesis pathway in the germline operates according to the same principles as the existing model for the soma, and its impairment does not significantly affect piRNAs. Expanding the analysis, we confirmed the occurrence of somatic piRNA-like RNAs (pilRNAs) that show a ping-pong signature. We detected expression of the Piwi-family protein mRNAs only barely above background, indicating that the somatic pilRNAs may arise from a small sub-population of somatic cells that express a functional piRNA pathway. Overall design: small RNA sampling experiment; small RNAs were prepared from head & thorax as well as dissected ovaries of Adult female Drosophila melanogaster. We used homozygous mutants of the dsRBD proteins Loqs and r2d2 to determine their contribution to the biogenesis of transposon-derived small RNAs. Heterozygous mutant animals served as control. For each RNA sample, we performed one deep-sequencing run without any treatment, and in parallel one sequencing run after periodate oxidation and beta-elimination. After this treatment, only Ago2, Piwi, Aub and Ago3-loaded small RNAs remain as they carry a 2''-O-methyl modification at their 3''-end. This helps to determine the loading status of the small RNAs detected. In total 8 different RNA samples were prepared and 16 libraries were sequenced.
Publication Title
Transposon defense by endo-siRNAs, piRNAs and somatic pilRNAs in Drosophila: contributions of Loqs-PD and R2D2.
Sample Metadata Fields
Specimen part, Subject
View Samples- Saccharomyces cerevisiae
- 8 Downloadable Samples
- Affymetrix Yeast Genome S98 Array (ygs98)
Description
The experiment describes the transcriptional response of Saccharomyces cerevisiae BY4741 and of the deletion mutant Δhaa1 following an incubation in the presence of 50 mM acetic acid (at pH 4.0)
Publication Title
Genomic expression program involving the Haa1p-regulon in Saccharomyces cerevisiae response to acetic acid.
Sample Metadata Fields
Compound
View Samples