Interferon alpha induced gene expression in SOCS1 and SOCS3 overexpressing melanoma and hepatoma cell lines.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22801 | GEO | 2012/12/31
SECONDARY ACCESSION(S): PRJNA127915
REPOSITORIES: GEO
Similar Datasets
Project description:Interferon-alpha (pegylated interferon and ribavirin) is used as standard-of-care therapeutic for chronic hepatitis C virus infection. Besides good cure in some patients other patients do not benefit from the treatment dependent on the virus type and host factors. One class of putative effector proteins is the family of Suppressors of cytokine signalling (SOCS). They act in a classical negative feedback-loop against the action of interferons and many other cytokines. It has been proven that some of them, in particular SOCS1 and SOCS3, inhibit the expression of interferon induced antiviral proteins. Their mode of action depends on the signal they are interfering with. In relation to the interferon-gamma pathway, they are thought to act on the interferon-alpha receptors by masking its recognition site for the Janus kinases (JAK), by blocking the kinase activity of the JAKs and coincidentally hindering STAT molecules from binding to the kinases. They are also thought to ubiquitinate the JAKs resulting in their proteosomal degradation. The function of SOCS proteins in suppressing the interferon-alpha pathway has not yet been characterized exhaustively. This study should unveil links to understand the resistance in interferon-alpha therapy. As results we got almost complete silencing of JAK-STAT signaling in SOCS1 over-expressing cells and tissue-dependent partially suppressed gene induction in SOCS3 over-expressing cell lines. Two human cancer cell lines (ME-15, HuH-7) were stably transfected with pcDNA3.1-SOCS plasmids in presence of geneticin and daughter cell lines were generated after singularization of cells. Next, original cell lines as well as SOCS1 and SOCS3 over-expressing cell lines were treated with 1000 U/ml interferon-alpha for 4 or 24 hours or in normal culture medium. Cells lines obtained from SOCS4 plasmid transfections were screened as additional control. Gene expression levels of cell cultured in control (0 for 4 hours, 2 for 24 hours) or interferon-alpha supplemented medium for 4 hours (1) or 24 hours (4) were analyzed. mRNA abundance was measured in triplicates using 12x8-sample commercial Illumina microarrays (HumanRef 8, version 3) and scanner system (iScan) as well as reagents recommend by Illumina (IlluminaM-BM-. TotalPrep Kit).
2012-12-31 | E-GEOD-22801 | biostudies-arrayexpress
Project description:We used microarrays to identify genes regulated during oncolytic HSV infection. Oncolytic herpes simplex viruses (oHSV) are promising anticancer therapeutics. We sought to identify alterations in gene expression during oHSV infection of human cancer cells. Human malignant peripheral nerve sheath tumor (MPNST) cells were infected with G207, an ICP34.5-deleted oHSV previously evaluated in clinical trials. G207-infected cells demonstrated massive degradation of cellular mRNAs, while a subset were upregulated. A gene signature of 21 oHSV-induced genes contained 7 genes known to be HSV-induced. Go ontology classification revealed that a majority of upregulated genes are involved in Jak/STAT signaling, transcriptional regulation, nucleic acid metabolism, protein synthesis and apoptosis. Ingenuity-defined functional networks highlighted nodes for AP-1 subunits and interferon signaling via STAT1, SOCS1, SOCS3 and RANTES. Upregulation of SOCS1 correlated with sensitivity of MPNST lines to G207 and depletion of SOCS1 reduced virus replication >1-log. The transcriptome of oHSV-induced genes may predict oncolytic efficacy and provides rationale for next generation oncolytics. Experiment Overall Design: 5 human MPNST cancer cell lines were infected with G207 or mock infected for 6 hours followed by RNA extraction and hybridization on Affymetrix microarrays.
2008-06-16 | E-GEOD-8717 | biostudies-arrayexpress
Project description:In maturing T-lineage cells, the helix-loop-helix protein E47 has been shown to enforce a critical proliferation and developmental checkpoint commonly referred to as β selection. To examine how E47 regulates cellular expansion and developmental progression, we have used an E2A deficient lymphoma cell line and DNA microarray analysis to identify immediate E47 target genes. Hierarchical cluster analysis of gene expression patterns revealed that E47 coordinately regulates the expression of genes involved in cell survival, cell growth, lipid metabolism, stress response and lymphoid maturation. These include Cdk6, CD25, Tox, Gadd45a, Gadd45b, Gfi1, Gfi1b, Socs1, Socs3, Id2, Eto2 and Xbp1. We propose a regulatory network linking JAK/STAT mediated signaling, E47 and SOCS proteins in a common pathway. Finally, we suggest that the aberrant activation of Cdk6 in E47 deficient T-lineage cells contributes to the development of lymphoid malignancy. Keywords: gene targets for E47
2006-05-09 | GSE4784 | GEO
Project description:We used microarrays to identify genes regulated during oncolytic HSV infection. Oncolytic herpes simplex viruses (oHSV) are promising anticancer therapeutics. We sought to identify alterations in gene expression during oHSV infection of human cancer cells. Human malignant peripheral nerve sheath tumor (MPNST) cells were infected with G207, an ICP34.5-deleted oHSV previously evaluated in clinical trials. G207-infected cells demonstrated massive degradation of cellular mRNAs, while a subset were upregulated. A gene signature of 21 oHSV-induced genes contained 7 genes known to be HSV-induced. Go ontology classification revealed that a majority of upregulated genes are involved in Jak/STAT signaling, transcriptional regulation, nucleic acid metabolism, protein synthesis and apoptosis. Ingenuity-defined functional networks highlighted nodes for AP-1 subunits and interferon signaling via STAT1, SOCS1, SOCS3 and RANTES. Upregulation of SOCS1 correlated with sensitivity of MPNST lines to G207 and depletion of SOCS1 reduced virus replication >1-log. The transcriptome of oHSV-induced genes may predict oncolytic efficacy and provides rationale for next generation oncolytics. Keywords: treated vs non treated
2007-08-08 | GSE8717 | GEO
Project description:NCBS Curation Comments:
This model shows the control mechanism of Jak-Stat pathway, here SOCS1 (Suppressor of cytokine signaling-I) was identified as the negative regulator of Jak and STAT signal transduction pathway. This is the knockout version of Jak-Stat pathway in this model the SOCS1 has been knocked out i.e it formation is not shown. The graphs are almost similar to the graphs as shown in the paper but STAT1n graph has some ambiguities. Thanks to Dr Satoshi Yamada for clarifying some of those ambiguities and providing the values used in simulations.
Biomodels Curation Comments:
The model reproduces the figures 2 (B,D,F,H,J,L,N) corresponding to JAK/STAT activation in SOCS1 knock out cells. The model was successfully tested on MathSBML
This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2006 The BioModels Team.
For more information see the terms of use
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2007-01-26 | BIOMD0000000094 | BioModels
Project description:Oral administration of nucleotide analogues and injection of interferon-alpha (IFNalpha) are used to achieve immediate suppression in replication of hepatitis B virus (HBV). Nucleotide analogs and IFNalpha inhibit viral polymerase activity and cause long-term eradication of the virus at least in part through removing covalently closed circular DNA (cccDNA) via induction of the APOBEC3 deaminases family of molecules, respectively. This study aimed to explore whether the orally administrable low molecular weight agent CDM-3008 (RO8191), which mimics IFNalpha through the binding to IFNalpha receptor 2 (IFNAR2) and the activation of the JAK/STAT pathway, can suppress HBV replication and reduce cccDNA levels. In primary cultured human hepatocytes, HBV DNA levels as well as cccDNA levels were decreased after CDM-3008-treatment in a dose-dependent manner with a half-maximal inhibitory concentration (IC50) value of 0.1 micro M, and this was accompanied by significant reductions in both HBeAg and HBsAg levels in the cell culture medium. Using a microarray we comprehensively analyzed and compared changes in gene (mRNA) expression in CDM-3008- and IFNalpha-treated primary cultured human hepatocytes. As reported previously, CDM-3008 mimicked the induction of molecules that participate in the interferon signaling pathway. OAS1 and ISG20 mRNA expression was similarly enhanced by both CDM-3008 and IFNalpha. Thus, CDM-3008 could suppress pgRNA expression to show anti-HBV activity. APOBEC3F and 3G mRNA expression was induced by CDM-3008 and IFNalpha treatment suggesting that cccDNA could be degraded through induced APOBEC3 family proteins. Finally, we identified the genes whose expression was specifically enhanced in CDM-3008-treated cells compared to IFNalpha-treated cells. The expression of SOCS1, SOCS2, SOCS3, and CISH, which inhibit STAT activation, was enhanced in CDM-3008-treated cells suggesting that a feedback inhibition of the JAK/STAT pathway was enhanced in CDM-3008-treated cells compared to IFNalpha-treated cells. In addition, CDM-3008 showed an additive effect with entecavir on inhibition of HBV replication. In summary, CDM-3008 showed anti-HBV activity through activation of the JAK/STAT pathway, inducing the expression of interferon-stimulated genes (ISGs), with greater feedback inhibition than IFNalpha.
2019-02-06 | GSE126090 | GEO
Project description:In maturing T-lineage cells, the helix-loop-helix protein E47 has been shown to enforce a critical proliferation and developmental checkpoint commonly referred to as β selection. To examine how E47 regulates cellular expansion and developmental progression, we have used an E2A deficient lymphoma cell line and DNA microarray analysis to identify immediate E47 target genes. Hierarchical cluster analysis of gene expression patterns revealed that E47 coordinately regulates the expression of genes involved in cell survival, cell growth, lipid metabolism, stress response and lymphoid maturation. These include Cdk6, CD25, Tox, Gadd45a, Gadd45b, Gfi1, Gfi1b, Socs1, Socs3, Id2, Eto2 and Xbp1. We propose a regulatory network linking JAK/STAT mediated signaling, E47 and SOCS proteins in a common pathway. Finally, we suggest that the aberrant activation of Cdk6 in E47 deficient T-lineage cells contributes to the development of lymphoid malignancy. We used the 1F9 cell line, originally isolated from E2A deficient thymomas. To identify E47 target genes, 1F9 cells were transduced with a retrovirus carrying an E47/estrogen receptor (E47ER) hybrid protein. Control cells were transduced with virus carrying the bHLH region but lacking the N-terminal transactivation domain. Both retroviral constructs also directed the expression of human CD25 (hCD25) to allow rapid isolation of transduced cells. One day post-infection, cells were incubated with 4-hydroxytamoxifen (4-OHT) for a period of six hours, to activate the E47ER fusion protein. hCD25 positive cells were purified using magnetic beads, RNA was isolated and used to generate probes for hybridization to murine oligonucleotide microarrays.
2010-07-01 | E-GEOD-4784 | biostudies-arrayexpress
Project description:Activation of the immune system is a way for host tissue to defend itself against tumor growth. Hence, treatment strategies that are based on immunomodulation are on the rise. Conventional cytostatic drugs such as the anthracycline doxorubicin can also activate immune cell functions of macrophages and natural killer cells. In addition, cytotoxicity of doxorubicin can be enhanced by combining this drug with the cytokine IFN-alpha. Although doxorubicin is one of the most applied cytostatics, the molecular mechanisms of its immunomodulation ability are not investigated thoroughly. In microarray analyses of HeLa cells, a set of 19 genes related to interferon signaling was significantly overrepresented among genes regulated by doxorubicin exposure including STAT-1, -2, IRF9, NMI, and caspase 1. Regulation of these genes by doxorubicin was verified with Real-Time PCR and immunoblotting. An enhanced secretion of IFN-alpha was observed when HeLa cells were exposed to doxorubicin as compared to untreated cells. IFN-alpha neutralizing antibodies and inhibitors of JAK-STAT signaling (ATA and AG490) significantly abolished doxorubicin-stimulated expression of interferon signaling-related genes. Furthermore, inhibition of JAK-STAT signaling significantly reduced doxorubicin induced caspase 3 activation and desensitized HeLa cells to doxorubicin cytotoxicity. In conclusion, we demonstrate that doxorubicin induces interferon-responsive genes via IFN-alpha-JAK-STAT1 signaling and that this pathway is relevant for doxorubicinM-bM-^@M-^Ys cytotoxicity in HeLa cells. As immunomodulation is a promising strategy in anticancer treatment, this novel mode of action of doxorubicin may help to further improve the use of this drug among different types of anticancer treatment strategies. One batch of HeLa Cell culture treated with doxorubicin and DMSO (control) were used for screening of global changes at the transcriptome level.
2012-05-22 | E-GEOD-30988 | biostudies-arrayexpress
Project description:Dysregulation of the JAK/STAT signaling pathway is associated with Multiple Sclerosis (MS) and its mouse model, Experimental Autoimmune Encephalomyelitis (EAE). Suppressors Of Cytokine Signaling (SOCS) negatively regulate the JAK/STAT pathway. We previously reported a severe, brain-targeted, atypical form of EAE in mice lacking Socs3 in myeloid cells (Socs3ΔLysM), which is associated with cerebellar neutrophil infiltration. There is emerging evidence that neutrophils are detrimental in the pathology of MS/EAE, however, their exact function is unclear. Here we demonstrate that neutrophils from the cerebellum of Socs3ΔLysM mice show a hyper-activated phenotype with excessive production of reactive oxygen species (ROS) at the peak of EAE. Neutralization of ROS in vivo delayed the onset and reduced severity of atypical EAE. Mechanistically, Socs3-deficient neutrophils exhibit enhanced STAT3 activation, a hyper-activated phenotype in response to G-CSF, and upon G-CSF priming, increased ROS production. Neutralization of G-CSF in vivo significantly reduced the incidence and severity of the atypical EAE phenotype. Overall, our work elucidates that hypersensitivity of G-CSF/STAT3 signaling in Socs3ΔLysM mice leads to atypical EAE by enhanced neutrophil activation and increased oxidative stress, which may explain the detrimental role of G-CSF in MS patients.
2019-05-04 | GSE122353 | GEO
Project description:This dataset is part of the paper: Pegylated interferon-α regulates hepatic gene expression by transient activation of the Jak-STAT pathway; Dill MT et al; Journal of Clinical Investigation; in review Pegylated interferon-α (pegIFN-α) has replaced un-modified recombinant IFN-α for the treatment of chronic viral hepatitis because of its superior anti-viral efficacy that is generally attributed to improved pharmacokinetic properties. However, the pharmacodynamic effects of pegIFN-α in the liver have not been studied. We analyzed pegIFN-α induced signaling and gene regulation in paired liver biopsies obtained before treatment and during the first week after injection of pegIFN-α in 18 patients. Despite sustained high serum concentrations of pegIFN-α over the entire one-week dosing interval, IFN-α signaling through the Jak-STAT pathway occurs only during the first day. PegIFN-α induces hundreds of genes that can be classified into 4 clusters based on different temporal expression profiles. In all clusters, gene transcription is mainly driven by IFN stimulated gene factor 3 (ISGF3). IFN induced secondary transcription factors do not cause additional waves of gene expression. We could not confirm a role of un-phosphorylated STAT1 in prolonging IFN-α induced gene transcription. Collectively, our results reveal that the major effects of pegIFN-α in the liver are caused by an early and transient activation of ISGF3. Prolonging the serum half-life of IFN-α does not necessarily improve its pharmacodynamic properties. Paired liver biopsy samples were collected before and during the first week of pegylated interferon alpha treatment of 21 chronic hepatitis C patients. Total: 21 patients and 42 samples. This dataset is part of the TransQST collection.
2014-01-30 | E-GEOD-48445 | biostudies-arrayexpress