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SRP087627
Homo sapiens
24 Downloadable Samples
Illumina HiSeq 2000
Description
Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal and tissue-restricted deletions have profound effects on erythroid development, cardiac function and neurogenesis. In addition, depletion of ERK5 is anti-inflammatory and anti-tumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no anti-inflammatory or anti-proliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains (BRDs), conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a non-catalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity, and delineate which can be pharmacologically targeted. Overall design: Two cellular models with reported ERK5-regulated signaling were used: Pam3CSK4-stimulated HUVECs as a model of inflammation, and EGF-stimulated HeLa cells as an established cell model of ERK5 regulation. Cells were pre-incubated with DMSO vehicle, AX15836 (ERK5 inhibitor), AX15839 (dual ERK5/BRD inhibitor), or I-BET762 (BRD inhibitor), then stimulated with agonist. Cellular responses were verified by immunoassays and western blots using replicate wells in the same experiment.
Publication Title
ERK5 kinase activity is dispensable for cellular immune response and proliferation.
Sample Metadata Fields
Specimen part, Subject, Compound
View Samples- Homo sapiens
- 9 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
To define the characteristics of human oral mucosa fibroblasts (hOFs), we analyzed the gene expression of hOFs compared with that of human dermal fibroblasts (hDFs), and that of hOF-derived induced pluripotent stem cells (hOF-iPSCs).
Publication Title
Gene Signature of Human Oral Mucosa Fibroblasts: Comparison with Dermal Fibroblasts and Induced Pluripotent Stem Cells.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Schizosaccharomyces pombe
- 3 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
Wild-type cells were cultured at 30 deg and cells were harvested. Total RNAs were purified from 3 populations.
Publication Title
Mapping of long-range associations throughout the fission yeast genome reveals global genome organization linked to transcriptional regulation.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and Fosb, encoding full-length FOSB and FOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and Fosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression.
Publication Title
Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- IlluminaHiSeq2000
Description
RNA-Seq analysis of SSA treated cells Overall design: HeLa cells, nuclear and cytoplasmic fractions, treated with SSA or MeOH
Publication Title
Global analysis of pre-mRNA subcellular localization following splicing inhibition by spliceostatin A.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 28 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
To examine fosB regulation of neurogenesis, depression and epilepsy, we compared the gene expression profiles of wild type, fosBd/d and fosB-null mice by microarray analysis.
Publication Title
fosB-null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
It remains controversial whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. We examined the gene expression and DNA methylation of 49 hiPSC and 10 hESC lines and identified no molecular signatures that distinguished hiPSCs from hESCs. Comparisons of the in vitro directed neural differentiation of 40 hiPSC and four hESC lines showed that most hiPSC clones were comparable to hESCs. However, in seven hiPSC clones, significant amount of undifferentiated cells persisted even after neural differentiation and resulted in teratoma formation when transplantated into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression of several genes, including those expressed from long terminal repeats of human endogenous retroviruses. These data demonstrated that many hiPSC clones are indistinguishable from hESCs, while some defective hiPSC clones need to be eliminated prior to their application for regenerative medicine.
Publication Title
Differentiation-defective phenotypes revealed by large-scale analyses of human pluripotent stem cells.
Sample Metadata Fields
Specimen part
View Samples- Pseudomonas aeruginosa pao1, Pseudomonas aeruginosa
- 8 Downloadable Samples
- Affymetrix Pseudomonas aeruginosa Array (paeg1a)
Description
The putative trancriptional regulator PA2449 was found to be essential for both glycine/serine metabolism and the production of phenazines in P. aeruignosa PAO1.
Publication Title
Gene PA2449 is essential for glycine metabolism and pyocyanin biosynthesis in Pseudomonas aeruginosa PAO1.
Sample Metadata Fields
No sample metadata fields
View Samples- Saccharomyces cerevisiae
- 18 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
We did transcription profiling on the effect of rlm1 (MAPK Slt2 transcription factor) deletion and swi3 (component of SWI/SNF complex involved in chromatin remodeling) deletion in genes involved in cell wall stress (Congo Red) response.
Publication Title
Chromatin remodeling by the SWI/SNF complex is essential for transcription mediated by the yeast cell wall integrity MAPK pathway.
Sample Metadata Fields
No sample metadata fields
View Samples