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SRP119759
Mus musculus
58 Downloadable Samples
NextSeq 500
Description
The study shows that RLRs drive distinct immune gene activation and polarization of the immune response. In our data, the RLR-dependent, WNV-induced immune response polarization overshadows the classical drivers of viral innate immune responses, interferon I (IFN) and IFN-stimulated genes, thus underscoring the importance of innate immune activation for channeling the adaptive immune system into specific effector pathways Overall design: We conducted genome-wide RNAseq and bioinformatics analysis of WNV infection in bone marrow derived macrophages from the RLR-deficient mice.
Publication Title
RIG-I-like receptors direct inflammatory macrophage polarization against West Nile virus infection.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Mus musculus
- 36 Downloadable Samples
Affymetrix Mouse Expression 430A Array (moe430a)
Description
Mouse embryonic fibroblasts (MEFs) were generated from 13.5-day-old embryos obtained from heterozygous PKBa mice intercrosses (Yang et al., 2003). Briefly, after dissection of head and visceral organs for genotyping, embryos were minced and trypsinized for 30 min at 37C. Embryonic fibroblasts were then plated and maintained in Dulbeccos Modified Eagle Medium (DMEM) with 10% foetal calf serum (FCS) (Life Technologies), 100 units/ml of penicillin and 100 mg/ml of streptomycin at 37C in an atmosphere of 5% CO2. All experiments were performed with wild-type and PKBa-/- MEFs between 15-20 passages. To induce adipocyte differentiation, 2-day-postconfluent cells (day 0) were treated with DMEM supplemented with 10% FCS, 8 mg/ml biotin, 4 mg/ml pantothenate, 0.5 mM 3-isobutyl-1-methylxanthine, 1 mM dexamethasone and 10 mg/ml insulin (all from Sigma). Total RNA was extracted from cells using TRIzol (Invitrogen) according to the manufacturers instructions.
Publication Title
PKBalpha is required for adipose differentiation of mouse embryonic fibroblasts.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Stage-specific sensitivity to p53 restoration during lung cancer progression.
Sample Metadata Fields
Sex, Specimen part, Cell line
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumor-suppressor pathways. The quest to personalize cancer medicine based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumor suppressors and activation of oncogenes are required for tumor maintenance. Mutations in the p53 tumor-suppressor pathway are a hallmark of cancer and significant efforts toward pharmaceutical reactivation of mutant p53 pathways are underway1-3. Here we show that restoration of p53 in established murine lung tumors leads to significant but incomplete tumor cell loss specifically in malignant adenocarcinomas but not in adenomas. Also, we define amplification of MAPK signaling as a critical determinant of malignant progression. The differential response to p53 restoration depends on activation of the Arf tumor suppressor downstream of hyperactive MAPK signaling. We propose that p53 naturally limits malignant progression by responding to increased oncogenic signaling, but is unresponsive to low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations.
Publication Title
Stage-specific sensitivity to p53 restoration during lung cancer progression.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Tumorigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumor-suppressor pathways. The quest to personalize cancer medicine based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumor suppressors and activation of oncogenes are required for tumor maintenance. Mutations in the p53 tumor-suppressor pathway are a hallmark of cancer and significant efforts toward pharmaceutical reactivation of mutant p53 pathways are underway1-3. Here we show that restoration of p53 in established murine lung tumors leads to significant but incomplete tumor cell loss specifically in malignant adenocarcinomas but not in adenomas. Also, we define amplification of MAPK signaling as a critical determinant of malignant progression. The differential response to p53 restoration depends on activation of the Arf tumor suppressor downstream of hyperactive MAPK signaling. We propose that p53 naturally limits malignant progression by responding to increased oncogenic signaling, but is unresponsive to low levels of oncogene activity that are sufficient for early stages of lung tumor development. These data suggest that restoration of pathways important in tumor progression, as opposed to initiation, may lead to incomplete tumor regression due to the stage-heterogeneity of tumor cell populations.
Publication Title
Stage-specific sensitivity to p53 restoration during lung cancer progression.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2000
Description
Inactivating mutations in the zinc finger gene PHF6 are seen in approximately 40% of adult T-cell acute lymphoblastic leukemias (T-ALLs) and 3% of adult acute myeloid leukemias (AMLs). The absence of PHF6 mutations in B-cell lineage malignancies has led to the hypothesis that PHF6 may act as a lineage-specific tumor suppressor gene. Here, we demonstrate that PHF6 plays a critical role in regulating B-cell identity in the context of B-cell precursor acute lymphoblastic leukemia (preB-ALL). Transplantation of Phf6 knockout preB-ALL cells (hereafter referred to as Phf6KO cells) into immunocompetent syngeneic recipients resulted in the development of a fully penetrant lymphoma-like disease. Strikingly, the resulting lymphomas showed robust up-regulation of the canonical T-cell marker CD4, suggesting that Phf6KO cells adopt a T-cell program in the context of leukemogenesis. RNA sequencing analysis revealed numerous differentially expressed (DE) genes in Phf6WT and Phf6KO cells, including a significant down-regulation of genes and gene sets involved in pathways important for B-cell development. Chromatin immunoprecipitation followed by high-throughput sequencing analysis revealed that PHF6 co-localizes with H3K27ac signals close to the transcription start sites (TSSs) and enhancer regions of a significant proportion of DE genes. Notably, regions flanking the TSS of DE genes showed significant enrichment for binding sites of several well-described master regulators of B-cell development, including PU.1, EGR-1, EBF-1, NF-kB, TCF3 and TCF12. We found that PHF6 and TCF12 physically interact in preB-ALL cells, suggesting that these factors act synergistically in the establishment and maintenance of B-cell identity. In addition, we found that a human PHF6 mutant T-ALL cell line has an incompletely rearranged IGH locus, strongly suggesting that T-ALL can have a B-cell origin. These findings reveal an essential role for PHF6 in the establishment and maintenance of B-cell identity in preB-ALL by directly activating genes that are crucial for B-cell lineage commitment and maintenance. Collectively, these results indicate that loss of function of PHF6 in preB-ALL leads to an unstable cellular state in which cells acquire alternate developmental programs (such as the T-lineage program) to survive, potentially explaining the apparent absence of PHF6 mutations in human B cell-lineage malignancies. Overall design: Gene expression profiles by RNA-Seq of 3 Phf6 wild-type preB-ALL cells, 3 shPhf6 preB-ALL cells, 6 Phf6 knockout (2 different sgRNAs) preB-ALL cells
Publication Title
PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The thymus constitutes the primary lymphoid organ for the majority of T cells. The phosphatidyl-inositol 3 kinase (PI3K) signaling pathway is involved in lymphoid development. Defects in single components of this pathway prevent thymocytes from progressing beyond early T cell developmental stages. Protein kinase B (PKB) is the main effector of the PI3K pathway. To determine whether PKB mediates PI3K signaling in early T cell development, we characterized PKB knockout thymi. Our results reveal a significant thymic hypocellularity in PKBalpha-/- neonates and an accumulation of early thymocyte subsets in PKBalpha-/- adult mice. The latter finding is specifically attributed to the lack of PKBalpha within the lymphoid component of the thymus. Microarray analyses show that the absence of PKBalpha in early thymocyte subsets modifies the expression of genes known to be involved in pre-TCR signaling, in T cell activation, and in the transduction of interferon-mediated signals. This report highlights the specific requirements of PKBalpha for thymic development.
Publication Title
Deletion of PKBalpha/Akt1 affects thymic development.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Glioblastoma multiforme (GBM) is the most malignant and most common tumor of the central nervous system characterized by rapid growth and extensive tissue infiltration. GBM results in more years of life lost than any other cancer type. Notch signaling has been implicated in GBM pathogenesis through several modes of action. Inhibition of Notch leads to a reduction of cancer-initiating cells in gliomas and reduces proliferation and migration. Deltex1 (DTX1) is part of an alternative Notch signaling pathway distinct from the canonical MAML1/RBPJ-mediated cascade. In this study, we show that DTX1 activates both the RTK/PI3K/PKB as well as the MAPK/ERK pathway. Moreover, we found the anti-apoptotic factor Mcl-1 to be induced by DTX1. In accordance with this, the clonogenic potential and proliferation rates of glioma cell lines correlated with DTX1 levels. DTX1 knock down mitigated the tumorigenic potential in vivo, and overexpression of DTX1 increased cell migration and invasion of tumor cells accompanied by an elevation of the pro-migratory factors PKB and Snail1. Microarray gene expression analysis identified a DTX1-specific transcriptional program - including microRNA-21 - which is distinct from the canonical Notch signaling. We propose the alternative Notch pathway via DTX1 as oncogenic factor in malignant glioma and found low DTX1 expression levels to correlate with prolonged survival of GBM and early breast cancer patients in open source databases.
Publication Title
Deltex-1 activates mitotic signaling and proliferation and increases the clonogenic and invasive potential of U373 and LN18 glioblastoma cells and correlates with patient survival.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 41 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
To identify signaling pathways that are differentially regulated in human gliomas, a microarray analysis on 30 brain tumor samples (12 primary glioblastomas (GBM), 3 secondary glioblastomas (GBM-2), 8 astrocytomas (Astro) and 7 oligodendrogliomas (Oligo)) and on 5 glioblastoma cell lines (LN018, LN215, LN229, LN319 and BS149) was performed. Normal brain tissue (NB) and normal human astrocytes (NHA) were used as a control. Kinase expression in each tumor was compared to expression in normal brain and expression values from normal human astrocytes were used as an additional control.
Publication Title
MAP kinase-interacting kinase 1 regulates SMAD2-dependent TGF-β signaling pathway in human glioblastoma.
Sample Metadata Fields
Sex, Age, Specimen part, Disease stage, Cell line
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Twist1 variants including wildtype Twist1, a non-phosphorylatable mutant Twist1/S42A and a phospho-mimicking mutant Twist1/S42D were expressed in 4T1 cells in which the endogenous Twist1 was depleted.
Publication Title
Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-β signaling axes.
Sample Metadata Fields
Specimen part
View Samples