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Expression data comparing the effect of IKK2 KO on a KRAS mouse model

ABSTRACT: Given that the NF-κB pathway plays an important role in tumor development and that IKK2 is the seminal kinase responsible for NF-κB pathway activation, we were particularly interested in exploring the therapeutic potential of IKK2 inhibition in non-small cell lung cancers. We crossed IKK2fl/fl and KrasG12D mice so that we could simultaneously activate KrasG12D to initiate tumor formation and inactivate IKK2, upon transduction by Cre lentiviral vectors. RNA isolated from finely dissected tumor nodules and tumor cell lines (4A3 and1D3) was applied to microarray analysis using Affymetrix Mouse Gene 1.0 STArrays according to the manufacturer’s instructions.

ORGANISM(S): Mus musculus

SUBMITTER: Eugene Ke

PROVIDER: E-GEOD-30049 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data comparing the effect of IKK2 KO on a KRAS mouse model

Project description:Given that the NF-κB pathway plays an important role in tumor development and that IKK2 is the seminal kinase responsible for NF-κB pathway activation, we were particularly interested in exploring the therapeutic potential of IKK2 inhibition in non-small cell lung cancers. We crossed IKK2fl/fl and KrasG12D mice so that we could simultaneously activate KrasG12D to initiate tumor formation and inactivate IKK2, upon transduction by Cre lentiviral vectors.

2011-12-15 | GSE30049 | GEO

Gene expression differences between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice

Project description:Constitutive Kras and NF-kappaB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms of constitutive NF-kappaB activation in KrasG12D-induced PDAC are not yet understood. Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kappaB activation and completely suppressed PDAC development in KrasG12D and KrasG12D;Ink4a/Arf mutant mice, demonstrating a genetic link between IKK2/beta and KrasG12D in PDAC inception. Our findings reveal that KrasG12D-activated AP-1 induces IL-1alpha, which in turn activates NF-kappaB and its target genes IL-1alpha and p62, to initiate IL-1alpha/p62 feedforward loops for inducing and sustaining NF-kappaB activity. Furthermore, IL-1alpha overexpression correlates with Kras mutation, constitutive NF-kappaB activity, and poor survival in PDAC patients. Therefore, our findings establish a pathway linking duel feedforward loops of IL-1alpha/p62 through which IKK2/beta/NF-kappaB is activated by KrasG12D. To study Kras-induced inflammatory responses and to identify differentially expressed genes between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice, cDNA microarray analysis was performed.

2012-01-24 | E-GEOD-27478 | biostudies-arrayexpress

Gene expression differences between the pancreatic tissues of Pdx1-Cre;KrasLSL-G12D and Pdx1-Cre;KrasLSL-G12D;IKK2/betaF/F mice

2012-01-24 | GSE27478 | GEO

Gene expression data from murine heart ventricles E12.5 with and without cardiomyocyte-specific expression of constitutively active IKK2

Project description:The transcription factor NF-κB has been associated with a range of pathological conditions of the heart, mainly based on its function as a master regulator of inflammation and pro-survival factor. Here, we addressed the question what effects activation of NF-κB can have during murine heart development. We expressed a constitutively active (CA) mutant of IKK2, the kinase activating canonical NF-κB signaling, specifically in cardiomyocytes under the control of the α-myosin heavy chain promoter. Expression of IKK2-CA resulted in embryonic lethality around E13. Embryos showed defects in compact zone formation and the contractile apparatus, and overall were characterized by widespread inflammation with infiltration of myeloid cells. Gene expression analysis at E12.5 suggested an interferon type I signature, with increased expression of interferon regulatory factors.

2015-10-14 | E-MTAB-3971 | biostudies-arrayexpress

Gene expresssion changes in pancreatic islets of 11 weeks old IKK2-CApdx-1 mice compared to control and Pdx-1+/- mice

2014-05-02 | GSE47504 | GEO

Gene expresssion changes in pancreatic islets of 11 weeks old IKK2-CApdx-1 mice compared to control and Pdx-1+/- mice

Project description:Canonical IKK/NF-κB signaling is a master regulator of inflammation and innate immunity and has been implicated in the pathogenesis of T1D. To investigate the impact of NF-κB activation on β-cell homeostasis and diabetes development, we generated a transgenic gain-of-function mouse model allowing conditional NF-κB activation via expression of IKK2-CA (constitutively active IKK2 allele) in β-cells using the tetracycline-regulated gene expression system. Pdx-1-tTA (knockin model generating Pdx-1 haploinsufficiency) driver mice were used for β-cell specific transgene expression. Double transgenic IKK2-CA-pdx-1 mice develop a full-blown immune-mediated diabetes.To identify gene expression changes underlying this diabetes development pancreatic islets of diabetic IKK2-CA-Pdx-1, PDX-1 +/- and control mice were prepared and isolated total RNA was used for microarray analysis. Pancreatic islets were isolated from 11 weeks old control (n=5), Pdx-1+/- (n=4) and IKK2-CApdx-1 (n=5) mice, total RNA was extracted with RNeasy mini kit (QIAGEN). Microarray analyses were performed using 200 ng total RNA as starting material and 5.5 µg ssDNA per hybridization (GeneChip Fluidics Station 450; Affymetrix, Santa Clara, CA). The total RNAs were amplified and labeled following the Whole Transcript (WT) Sense Target Labeling Assay (http://www.affymetrix.com). Labeled ssDNA was hybridized to Mouse Gene 1.0 ST Affymetrix GeneChip arrays (Affymetrix, Santa Clara, CA). The chips were scanned with a Affymetrix GeneChip Scanner 3000 and subsequent images analyzed using Affymetrix® Expression Console Software (Affymetrix). Probe level data were obtained using the robust multichip average (RMA) normalization algorithm.

2014-05-02 | E-GEOD-47504 | biostudies-arrayexpress

Transcription profiling by array of murine cardiomyocytes with and without expression of constitutively active IKK2

Project description:Inflammation is a major factor in heart disease. IÎºB kinase (IKK) and its downstream target NF-ÎºB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-ÎºB function in the heart by a gain-of-function approach, generating an inducible transgenic mouse model with cardiomyocyte-specific expression of constitutively active IKK2 (IKK2-CA). In adult animals, IKK2 activation led to inflammatory dilated cardiomyopathy and heart failure. Transgenic hearts showed infiltration with CD11b+ cells, fibrosis, fetal reprogramming, and atrophy of myocytes with strong constitutively active IKK2 expression. To gain insight into proximal events after activation of IKK2/NF-ÎºB, we isolated cardiomyocytes and activated the transgene in vitro, thus avoiding interference of other cell types. Gene expression analysis revealed up-regulation of transcripts of chemotactic cytokines, adhesion molecules, and a striking number of IFN-regulated genes in cardiomyocytes expressing IKK2-CA. In addition, apoptotic and anti-apoptotic genes were up-regulated.

2015-10-19 | E-MTAB-3975 | biostudies-arrayexpress

Expression data of transduced mouse glioblastomas

Project description:Transgenic GFAP-, NES-, and SYN- CRE mice were injected with a lenti-viral construct containing a floxed RFP directly upstream of a cassette containing si-p53, GFP, and mutant HRAS. Tumors arising from the various CRE tissue specific promoters and differing injections sites were compared to normal hippocampus and cortex. RNA was isolated from dissected tumors and applied to microarray anaylsis using Affymetrix Mouse Gene 1.0 ST Arrays according to manufactures instructions

2012-10-18 | E-GEOD-35917 | biostudies-arrayexpress

NEMO is distinct from IKK2 by regulating non-canonical pathway in the experimental nephrotoxic serum nephritis mouse model

Project description:Experimental nephrotoxic serum nephritis (NTN) is a model for T-cell mediated human rapid progressive glomerulonephritis. T-cell receptor (TCR) stimulation leads to intracellular signaling events ultimately causing activation of transcription factors, such as NF-κB. Using CD4creIKK2fl/fl (CD4xIKK2Δ) and CD4creNEMOfl/fl (CD4xNEMOΔ) and CD4cre mice our results demonstrated that NTN was not attenuated in CD4xIKK2Δ, CD4xNEMOΔ when compared with CD4cre mice as showing no significant kidney functional difference with respect to BUN and proteinuria data as well as histological damage. Although the percentage of CD4+ T cells infiltrating kidneys was not significantly changed between the examined groups on day 10, further analysis showed significantly reduced Tregs and significant increase in Th1 and Th17 cells in CD4xIKK2Δ and CD4xNEMOΔ mice. The expression of renal cytokines and chemokines, IL-1β, CCL2 and CCL20, was significantly changed in CD4xIKK2Δ and CD4xNEMOΔ mice when compared with nephritic CD4cre animals. The microarray data confirmed the increased expression of Th17 related cytokines in splenetic CD4+ T cells. More importantly, our array data also demonstrated the interrupted canonical pathway in nephritic CD4xNEMOΔ mice, which highlighted the possible different downstream pathway when IKK2 or NEMO is specifically deleted in lymphocytes. By combining microarray gene expression and bioinformatics analyses our data have identified genes involved in T cell proliferation and differentiation that were differentially expressed between IKK2 and NEMO deficient CD4+ T cells. We propose that better understanding the role of IKK2 and NEMO in T cell regulation will help to recognize the role of IKK2 and NEMO kinase inhibitors in the clinical application in patients with glomerulonephritis.

2018-11-30 | GSE107364 | GEO

Gene expression analysis between the pancreatic tissues of Pdx1-cre;Kras LSL-G12D and Pdx-cre;KrasLSL-G12D;IKK2/beta F/F mice

Project description:Constitutive Kras and NF-kB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kB activation and completely suppressed PDAC development. Our findings demonstrated that NF-kB is required for development of pancreatic ductal adenocarcinoma that was initiated by Kras activation.

2012-01-24 | GSE33322 | GEO

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