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Mus musculus
6 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Mitogen-activated protein kinase kinase 4 (MKK4) is a dual-specificity kinase activated by environmental stress, cytokines, and peptide growth factors that reportedly can promote or inhibit tumor cell growth and metastasis. Somatic mutations in the gene encoding MKK4 (MAP2K4) have been identified in various human cancers, but the consequences of these mutations on MKK4 function and the biology of tumor cells that have them have not been elucidated. Here we report that, of the eleven mutations within the MAP2K kinase domain described thus far, one had gain-of-function (Q142L) and six had loss-of-function. Three of the loss-of-function mutations are nonsense mutations that produced C-terminally-truncated proteins (I295fs*23, R304*, and W310*) that were highly ubiqitinated and rapidly degraded when introduced into cells, and three are missense mutations in the ATP-binding pocket (N234I), activation loop (S251N), or C-lobe (P326L). We modeled the consequences of MAP2K4 loss-of-function mutations on cells by introducing MKK4 short-hairpin RNA constructs and found that MKK4 depletion enhanced the ability of a weakly tumorigenic murine cancer cell to metastasize when injected into syngeneic mice but had no effect on primary tumor formation. MKK4-depleted cells exhibited an increased capacity to migrate across PET filters and to invade through matrigel but no change in anchorage-dependent or -independent proliferation. Transcriptional profiling of these cells revealed gene expression changes that promote epithelial-to-mesenchymal transition and angiogenesis. We conclude that MKK4 inactivation promoted metastasis but not primary tumor formation. Collectively, these findings implicate loss-of-function MAP2K4 somatic mutations in tumor metastasis and provide one of the few examples of a somatic mutation in cancer cells that exerts a metastasis-specific effect.
Publication Title
Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor γ2 expression.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Mouse liver tumors (T) and non tumoral adjacent livers (NT) sorted from mice knock out for Axin1 gene specifically in the hepatocytes . 3 mice of the brother hood non deleted for Axin1 were used as controls (WT)
Publication Title
AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of β-catenin activation.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
Illumina HiSeq 2500
Description
Regulatory T cells (Tregs) expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance1-5; yet, excessive Treg activities suppress anti-tumor immune responses6-8. Compared to resting phenotype Tregs (rTregs) in the secondary lymphoid organs, Tregs in non-lymphoid tissues including solid tumors exhibit an activated Treg (aTreg) phenotype9-11. However, aTreg function and whether its generation can be manipulated to promote tumor immunity without evoking autoimmunity are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg suppression of lymphoproliferative diseases12,13, has an unexpected function in inhibiting aTreg-mediated immune tolerance. We found that aTregs turned over at a slower rate than rTregs, but were not locally maintained in tissues. Transcriptome analysis revealed that aTreg differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic Foxo1 localization, and enhanced Foxo1 phosphorylation at sites of the Akt kinase. Treg-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg homing to non-lymphoid organs, causing CD8+ T cell-mediated autoimmune diseases. Compared to Tregs from healthy tissues, tumor-infiltrating Tregs downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumor-associated Tregs, activate effector CD8+ T cells, and inhibit tumor growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTregs that have a crucial function in suppressing CD8+ T cell responses; and the Foxo signaling pathway in Tregs can be titrated to preferentially break tumor immune tolerance. Overall design: Transcriptome of splenic rTreg (CD4+Foxp3+CD62LhiCD44lo) and aTreg (CD4+Foxp3+CD62LhiCD44lo) were compared. Duplicates from biologically independent animials were used.
Publication Title
Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarrays to compared gene expression profilings in various tumors of the kidney.
Publication Title
Balanced Translocations Disrupting SMARCB1 Are Hallmark Recurrent Genetic Alterations in Renal Medullary Carcinomas.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Ets transcription factor GABP controls T cell homeostasis and immunity.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Ets family transcription factor GA-binding protein (GABP) regulates gene expression in CD4 and CD8 T cells.
Publication Title
Ets transcription factor GABP controls T cell homeostasis and immunity.
Sample Metadata Fields
Specimen part
View Samples- Arabidopsis thaliana
- 9 Downloadable Samples
- Arabidopsis Gene 1.1 ST Array (aragene11st)
Description
Transcript profiling analysis of Hydraulic conductivity of Root 1 (HCR1) mutant compared to wild type (Col-0) using ARABIDOPSIS GENE1.1ST ARRAY STRIP (901793, Affymetrix, Santa Clara, USA).
Publication Title
A Potassium-Dependent Oxygen Sensing Pathway Regulates Plant Root Hydraulics.
Sample Metadata Fields
Age, Specimen part
View Samples
GSE63862- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
In order to understand the transcriptional effects of CD44s expression in a cell line that does not express CD44 in its native form we transfected CD44s into HEK cells and measured the transcriptional chances compared to native HEK cells
Publication Title
CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Alterations of chromatin modifiers are frequent in cancer but their functional consequences remain often unclear. Focusing on the Polycomb protein EZH2 that deposits H3K27me3 mark, we showed that its high expression in solid tumors is a consequence, and not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process is malfunctioning in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes are actually of poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes consequent to EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications.
Publication Title
Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Polycomb Repressive Complex 2 (PRC2) plays a key role in controlling transcriptional repression. It is thought to act at the level of the chromatin, where its enzymatic subunits Ezh1 and Ezh2 catalyse the di/tri-methylation of histone H3 on its lysine 27 (H3K27me3).
Publication Title
Impaired PRC2 activity promotes transcriptional instability and favors breast tumorigenesis.
Sample Metadata Fields
Specimen part
View Samples