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GSE62477
Homo sapiens
18 Downloadable Samples
Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
Maternal Embryonic Leucine Zipper Kinase (MELK), a Ser/Thr protein kinase, is highly over expressed in stem and cancer cells. The oncogenic role of MELK is attributed to its capacity to disable critical cell cycle checkpoints and to enhance replication. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing, but this is often compromised by off target effects. Here we present the cellular validation of a novel, potent and selective small molecule MELK inhibitor, MELK-T1, which has enabled us to explore the biological function of MELK. Strikingly, the binding of MELK-T1 to endogenous MELK triggers a rapid and proteasome dependent degradation of the MELK protein. Treatment of MCF-7 breast adenocarcinoma cells with MELK-T1 leads to an accumulation of stalled replication forks and double strand breaks, followed by a replicative senescence phenotype. This phenotype correlates with a rapid and long-lasting ATM activation and phosphorylation of CHK2. Furthermore, MELK-T1 induces strong phosphorylation of p53 and prolonged up-regulation of p21.
Publication Title
MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 8 Downloadable Samples
NextSeq 500
Description
This study aimed to explore the role of NIPP1 in adult germline cell proliferation and differentiation, using a ubiquitous inducible NIPP1 knockout (TKO) mouse model. To gain unbiased insight into the molecular mechanism that underly the sertoli-only phenotype in TKO, we performed a comparative RNA sequencing profiling of control and TKO, in which NIPP1 was tamoxifin-induced depleted. Overall design: Two genotypes are compared after treatment with tamoxifen. The control genotype (UBC CRE-ERT2+/- Ppp1r8 fl/+) looses the floxed allele of PPP1R8 (aka NIPP1) as a consequence of the treatment with tamoxifen and becomes heterozygous for PPP1R8. The KO genotype (UBC CRE-ERT2+/- Ppp1r8 fl/-) also looses the floxed allele of PPP1R8 as a consequence of the tamoxifen treatment and becomes homozygous KO. For each genotype, 4 replicates are profiled.
Publication Title
The protein phosphatase 1 regulator NIPP1 is essential for mammalian spermatogenesis.
Sample Metadata Fields
Age, Specimen part, Subject
View Samples- Homo sapiens
- 36 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that is characterized by the presence of inflammatory cytokines, including interleukin-6 (IL-6). Here, we investigated the global molecular effects of Tocilizumab, an approved humanized anti-IL6 Receptor antibody, versus Methotrexate therapy, in synovial biopsy samples collected prospectively in early RA before and 12 weeks after administration of the drug. The results were compared with our previous data, generated in prospective cohorts of Adalimumab- and Rituximab-treated (Methotrexate- and anti-TNF-resistant, respectively) RA patients.
Publication Title
Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 23 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Objective: Rituximab displays therapeutic benefits in the treatment of rheumatoid arthritis (RA) patients resistant to TNF blockade. However, the precise role of B cells in the pathogenesis of RA is still unknown. In this study we investigated the global molecular effects of rituximab in synovial biopsies obtained from anti-TNF resistant RA patients before and after administration of the drug.
Publication Title
Rituximab treatment induces the expression of genes involved in healing processes in the rheumatoid arthritis synovium.
Sample Metadata Fields
Sex, Specimen part, Disease, Disease stage, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
TNF antagonists are routinely used in severe rheumatoid arthritis (RA) patients who failed conventional DMARD therapy. According to large clinical trials, the three available drugs (adalimumab, infliximab and etanercept) display similar effects in terms of efficacy, tolerability and side effects. These studies also indicate that about 25% of RA patients treated with TNF-antagonists do not display any significant clinical improvement.
Publication Title
Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis.
Sample Metadata Fields
Specimen part, Disease
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
TNFalpha and IL1beta play a pathogenic role in rheumatoid arthritis. Both cytokines are known to activate cytokine and metalloproteinase secretion by synovial fibroblasts. In the present study, we wanted to investigate whether TNFalpha and IL1beta displayed differential effects on cultured Fibroblast-like Synovial Cells derived from RA patients. Global gene expression analyses indicated that both cytokines induced similar genes in these cells.
Publication Title
Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis.
Sample Metadata Fields
Specimen part, Disease, Treatment
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We found that Hopx is required for the function of DC-induced regulatory T cells in vivo. We used microarrays to identify relevant Hopx-targets in such cells after antigenic re-challenge in vivo.
Publication Title
The transcription cofactor Hopx is required for regulatory T cell function in dendritic cell-mediated peripheral T cell unresponsiveness.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Illumina HiSeq 2000
Description
The success of targeted therapies hinges on our ability to understand the molecular and cellular mechanism of action of these agents. Here we modify various BET bromodomain inhibitors, an exemplar novel targeted therapy, to create functionally conserved compounds that are amenable to click-chemistry and can be used as molecular probes in vitro and in vivo. Using click-proteomics and click-sequencing we provide new mechanistic insights to explain the gene regulatory function of BRD4 and the transcriptional changes invoked by BET inhibitors. In mouse models of acute leukaemia, we use high resolution microscopy and flow cytometry to highlight the underappreciated heterogeneity of drug activity within tumour cells located in different tissue compartments. We also demonstrate the differential distribution and effects of the drug in normal and malignant cells in vivo. These data provide critical insights that reveal the cellular and molecular details for the efficacy and limitations of these agents. This study provides a framework for the pre-clinical assessment of other conventional and targeted therapies. Overall design: RNASeq of MV4;11 cell treated with DMSO, JQ1 or JQ1–PA
Publication Title
Click chemistry enables preclinical evaluation of targeted epigenetic therapies.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina Genome Analyzer
Description
Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the anti-inflammatory properties of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a serious problem in the management of inflammatory diseases and occurs frequently. The strong pro-inflammatory cytokine TNF induces an acute form of GCR, not only in mice, but also in several cell lines, e.g. in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-induced GR-dependent gene expression. We report that TNF has a significant and broad impact on the transcriptional performance of GR, but no impact on nuclear translocation, dimerization or DNA binding capacity of GR. Proteome-wide proximity-mapping (BioID), however, revealed that the GR interactome is strongly modulated by TNF. One GR cofactor that interacts significantly less with the receptor under GCR conditions is p300. NF?B activation and p300 knockdown both reduce transcriptional output of GR, whereas p300 overexpression and NF?B inhibition revert TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis is supported by FRET studies. This mechanism of GCR opens new avenues for therapeutic interventions in GCR diseases Overall design: Examination of GR induced gene expression in 4 conditions (1 control: NI and 3 treated: DEX, TNF, TNFDEX) starting from 3 biological replicates
Publication Title
TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Arabidopsis thaliana
- 9 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
This experiment was set up in order to identify the (direct) transcriptional targets of the Ethylene Response Factor 115 (ERF115) transcription factor. Because ERF115 expression occurs in quiescent center (QC) cells and strong effects on the QC cells were observed in ERF115 overexpression plants, root tips were harvested for transcript profiling in order to focus on root meristem and QC specific transcriptional targets.
Publication Title
ERF115 controls root quiescent center cell division and stem cell replenishment.
Sample Metadata Fields
Age, Specimen part
View Samples