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GSE35230
Homo sapiens
31 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
In an effort to understand the mechanisms of acquired resistance to BRAF inhibitors, we isolated clones that acquired resistance to the BRAF inhibitor GSK2118436 derived from the A375 BRAF V600E mutant melanoma cell line. This resistance clones acquired mutations in NRAS and MEK1. One clones, 16R6-4, acquired two mutations in NRAS Q61K and A146T. Proliferation and western blot analyses demonstrated that these clones were insensitive to single agent GSK2118436 or GSK1120212 (an allosteric MEK inhibitor) but were sensitive to the combination of GSK2118436 and GSK1120212. To further characterize this combination, global transcriptomic analysis was performed in A375 and 16R6-4 after 24 hour treatment with GSK2118436, GSK1120212 or the combination of GSK2118436 and GSK1120212.
Publication Title
Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 13 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, 6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD.
Publication Title
Hemidesmosome integrity protects the colon against colitis and colorectal cancer.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Transcriptome analysis of mRNAs extracted from the rectal mucosa of WT and 6IEC-TAM mice, 15 days after tamoxifen treatment
Publication Title
Hemidesmosome integrity protects the colon against colitis and colorectal cancer.
Sample Metadata Fields
Sex, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
Myotonic dystrophes (DM), the most common adult muscular dystrophy, are the first recognized examples of RNA-mediated diseases in which expression of mutant RNAs containing expanded CUG or CCUG repeats interfere with the splicing of other mRNAs. Using whole-genome microarrays, we found that alternative splicing of the BIN1 mRNA is altered in DM skeletal muscle tissues, resulting in the expression of an inactive form of BIN1 deprived of phosphoinositide-binding and membrane-tubulating activities. BIN1 is involved in tubular invaginations of the plasma membrane and is essential for biogenesis of the muscle T-tubules, which are specialized skeletal muscle membrane structures essential to correct excitation-contraction (E-C) coupling. Mutations in the BIN1 gene cause centronuclear myopathy (CNM) that shares some histopathological features with DM, and both diseases are characterized by muscle weakness. Consistent with a loss-of-function of BIN1, muscle T-tubules were altered in DM patients, and membrane tubulation was restored upon expression of the correct splicing form of BIN1 in DM muscle cells. By deciphering the mechanism of BIN1 splicing mis-regulation we demonstrate that the splicing regulator, MBNL1, which is sequestered by expanded CUG and CCUG in DM, binds the BIN1 pre-mRNA and regulates directly its alternative splicing. Finally, reproducing BIN1 splicing alteration in mice is sufficient to reproduce the DM features of T-tubule alterations and muscle weakness. We propose that alteration of BIN1 alternative splicing regulation leads to muscle weakness, a predominant pathological feature of DM.
Publication Title
Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
MicroRNAs (miRNAs) are short noncoding RNA molecules regulating the expression of mRNAs. Target identification of miRNAs is computationally difficult due to the relatively low homology between miRNAs and their targets. We provide data here utilizing an experimental approach to identify targets of mmu-miR-378-3p, where mmu-miR-378-3p was overexpressed and silenced in NIH-3T3 murine fibroblasts and compared to control RNA transfected cells (RISC-free siRNA). Expression of mRNAs was profiled and differentially expressed genes following either treatment as compared to control transfected cells were identified. In this way we identified 491 significantly differentially expressed genes with more than 1.4 fold change in either comparison. One of the putative targets Akt-1 was subsequently confirmed by luciferase reporter assay.
Publication Title
Induction of IL-4Rα-dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4-driven murine macrophage proliferation in vivo.
Sample Metadata Fields
Specimen part, Cell line
View Samples