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  1. Article: STAT Signaling in Glioma Cells.

    Swiatek-Machado, Karolina / Kaminska, Bozena

    Advances in experimental medicine and biology

    2020  Volume 1202, Page(s) 203–222

    Abstract: STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the ... ...

    Abstract STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.
    MeSH term(s) Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Transformation, Neoplastic ; Glioma/metabolism ; Glioma/pathology ; Humans ; Janus Kinases/metabolism ; Phosphorylation ; STAT Transcription Factors/metabolism ; Signal Transduction
    Chemical Substances STAT Transcription Factors ; Janus Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2020-02-07
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
    DOI 10.1007/978-3-030-30651-9_10
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: STAT signaling in glioma cells.

    Swiatek-Machado, Karolina / Kaminska, Bozena

    Advances in experimental medicine and biology

    2013  Volume 986, Page(s) 189–208

    Abstract: STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the ... ...

    Abstract STAT (signal transducers and activators of transcription) are latent cytoplasmic transcription factors that function as downstream effectors of cytokine and growth factor receptor signaling. The canonical JAK/STAT signaling pathway involves the activation of Janus kinases (JAK) or growth factors receptor kinases, phosphorylation of STAT proteins, their dimerization and translocation into the nucleus where STATs act as transcription factors with pleiotropic downstream effects. STAT signaling is tightly controlled with restricted kinetics due to action of its negative regulators. While STAT1 is believed to play an important role in growth arrest and apoptosis, and to act as a tumor suppressor, STAT3 and 5 are involved in promoting cell cycle progression, cellular transformation, and preventing apoptosis. Aberrant activation of STATs, in particular STAT3 and STAT5, have been found in a large number of human tumors, including gliomas and may contribute to oncogenesis. In this chapter, we have (1) summarized the mechanisms of STAT activation in normal and malignant signaling; (2) discussed evidence for the critical role of constitutively activated STAT3 and STAT5 in glioma pathobiology; (3) disclosed molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in gliomas.
    MeSH term(s) Animals ; Brain Neoplasms/metabolism ; Cell Line, Tumor ; Glioma/metabolism ; Humans ; STAT1 Transcription Factor/metabolism ; Signal Transduction
    Chemical Substances STAT1 Transcription Factor
    Language English
    Publishing date 2013
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
    DOI 10.1007/978-94-007-4719-7_10
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Targeting signaling pathways with small molecules to treat autoimmune disorders.

    Kaminska, Bozena / Swiatek-Machado, Karolina

    Expert review of clinical immunology

    2008  Volume 4, Issue 1, Page(s) 93–112

    Abstract: Chronic activation of immune responses, mediated by inflammatory mediators and involving different effector cells of the innate and acquired immune system characterizes autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, ... ...

    Abstract Chronic activation of immune responses, mediated by inflammatory mediators and involving different effector cells of the innate and acquired immune system characterizes autoimmune disorders, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and septic shock syndrome. MAPKs are crucial intracellular mediators of inflammation. MAPK inhibitors are attractive anti-inflammatory drugs, because they are capable of reducing the synthesis of inflammation mediators at multiple levels and are effective in blocking proinflammatory cytokine signaling. Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway converts cytokine signals into genomic responses regulating proliferation and differentiation of the immune cells. JAK inhibitors are a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory and antiallergic properties. This review discusses the rationale behind current strategies of targeting MAPK and JAK/STAT signaling pathways, and the overall effects of signal transduction inhibitors in animal models of inflammatory disorders. Signal transduction inhibitors are small molecules that can be administered orally, and initial results of clinical trials have shown clinical benefits in patients with chronic inflammatory disorders.
    Language English
    Publishing date 2008-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 2274260-8
    ISSN 1744-8409 ; 1744-666X
    ISSN (online) 1744-8409
    ISSN 1744-666X
    DOI 10.1586/1744666X.4.1.93
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Identification of pathway deregulation--gene expression based analysis of consistent signal transduction.

    Mieczkowski, Jakub / Swiatek-Machado, Karolina / Kaminska, Bozena

    PloS one

    2012  Volume 7, Issue 7, Page(s) e41541

    Abstract: Signaling pathways belong to a complex system of communication that governs cellular processes. They represent signal transduction from an extracellular stimulus via a receptor to intracellular mediators, as well as intracellular interactions. ... ...

    Abstract Signaling pathways belong to a complex system of communication that governs cellular processes. They represent signal transduction from an extracellular stimulus via a receptor to intracellular mediators, as well as intracellular interactions. Perturbations in signaling cascade often lead to detrimental changes in cell function and cause many diseases, including cancer. Identification of deregulated pathways may advance the understanding of complex diseases and lead to improvement of therapeutic strategies. We propose Analysis of Consistent Signal Transduction (ACST), a novel method for analysis of signaling pathways. Our method incorporates information regarding pathway topology, as well as data on the position of every gene in each pathway. To preserve gene-gene interactions we use a subject-sampling permutation model to assess the significance of pathway perturbations. We applied our approach to nine independent datasets of global gene expression profiling. The results of ACST, as well as three other methods used to analyze signaling pathways, are presented in the context of biological significance and repeatability among similar, yet independent, datasets. We demonstrate the usefulness of using information of pathway structure as well as genes' functions in the analysis of signaling pathways. We also show that ACST leads to biologically meaningful results and high repeatability.
    MeSH term(s) Animals ; Gene Expression Regulation/physiology ; Humans ; Models, Biological ; Signal Transduction/physiology
    Language English
    Publishing date 2012-07-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0041541
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Signal transducer and activator of transcription 1 (Stat1) maintains basal mRNA expression of pro-survival stat3-target genes in glioma C6 cells.

    Adach-Kilon, Alicja / Swiatek-Machado, Karolina / Kaminska, Bozena / Dabrowski, Michal

    Journal of cellular biochemistry

    2011  Volume 112, Issue 12, Page(s) 3685–3694

    Abstract: The STAT proteins (signal transducers and activators of transcription) are transcription factors mediating cytokine/growth factor signaling, which play important role in controlling cell cycle progression and apoptosis. In many cancer cell lines and ... ...

    Abstract The STAT proteins (signal transducers and activators of transcription) are transcription factors mediating cytokine/growth factor signaling, which play important role in controlling cell cycle progression and apoptosis. In many cancer cell lines and tumors (including gliomas) the STAT proteins (in particular Stats 1, 3, and 5) are persistently activated. In this study, we employed DNA decoys, siRNAs, and protein overexpression, to elucidate the role of Stat1 and Stat3 in regulation of expression of endogenous Stat3-target genes (Bcl2l1, Myc, Ccnd1) and a Stat-driven reporter plasmid, in rat C6 glioma cells. The results obtained with the decoys and siRNA suggest that in proliferating C6 cells, Stat1 supports the basal expression of Bcl2l1, while the decoy and chromatin immunoprecipitation results suggest it also plays a similar role for Myc. In the Stat-driven reporter system, overexpression of Stat1 stimulated, while overexpression of Stat3 inhibited the reporter gene expression. The level of Stat1 phosphorylation observed under basal conditions in proliferating glioma C6 cells is very low. Therefore, we speculate that it is the activity of the unphosphorylated Stat1 that is inhibited by Stat1 decoy or Stat1 siRNA. Taken together, our results demonstrate that it is Stat1 not Stat3 that maintains the expression of Bcl2l1 and possibly Myc in proliferating glioma C6 cells. An established paradigm is that Stat3 exerts a pro-survival and potentially oncogenic effects, while Stat1 is mainly associated with the immune response. Our results add to a number of reports that challenge this paradigm.
    MeSH term(s) Animals ; Base Sequence ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; DNA Primers ; Glioma/genetics ; Glioma/pathology ; Phosphorylation ; RNA, Messenger/genetics ; Rats ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; STAT1 Transcription Factor/metabolism ; STAT1 Transcription Factor/physiology ; STAT3 Transcription Factor/genetics
    Chemical Substances DNA Primers ; RNA, Messenger ; STAT1 Transcription Factor ; STAT3 Transcription Factor ; Stat1 protein, rat ; Stat3 protein, rat
    Language English
    Publishing date 2011-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.23305
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1114: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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  6. Article: Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells.

    Kruczyk, Marcin / Przanowski, Piotr / Dabrowski, Michal / Swiatek-Machado, Karolina / Mieczkowski, Jakub / Wallerman, Ola / Ronowicz, Anna / Piotrowski, Arkadiusz / Wadelius, Claes / Kaminska, Bozena / Komorowski, Jan

    Biochimica et biophysica acta

    2014  Volume 1839, Issue 11, Page(s) 1341–1350

    Abstract: Background: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune ... ...

    Abstract Background: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown.
    Results: We used chromatin immunoprecipitation, promoter microarrays and deep sequencing to assess the genome-wide occupancy of phospho (p)-Stat3 and epigenetic modifications of H3K4me3 and H3ac in C6 glioma cells. This combined assessment identified a list of 1200 genes whose promoters have both Stat3 binding sites and epigenetic marks characteristic for actively transcribed genes. The Stat3 and histone markings data were also intersected with a set of microarray data from C6 glioma cells after inhibition of Jak2/Stat3 signaling. Subsequently, we found 284 genes characterized by p-Stat3 occupancy, activating histone marks and transcriptional changes. Novel genes were screened for their potential involvement in oncogenesis, and the most interesting hits were verified by ChIP-PCR and STAT3 knockdown in human glioma cells.
    Conclusions: Non-random association between silent genes, histone marks and p-Stat3 binding near transcription start sites was observed, consistent with its repressive role in transcriptional regulation of target genes in glioma cells with specific genetic background.
    MeSH term(s) Animals ; Binding Sites/genetics ; Chromatin Immunoprecipitation ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic ; Glioma/genetics ; Glioma/metabolism ; Oligonucleotide Array Sequence Analysis ; Phosphorylation ; Protein Binding ; Rats ; STAT3 Transcription Factor/metabolism ; STAT3 Transcription Factor/physiology ; Transcription Initiation Site ; Transcriptome ; Tumor Cells, Cultured
    Chemical Substances STAT3 Transcription Factor ; Stat3 protein, rat
    Language English
    Publishing date 2014-11
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbagrm.2014.07.010
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  7. Article ; Online: Novel small molecular inhibitors disrupt the JAK/STAT3 and FAK signaling pathways and exhibit a potent antitumor activity in glioma cells.

    Swiatek-Machado, Karolina / Mieczkowski, Jakub / Ellert-Miklaszewska, Aleksandra / Swierk, Piotr / Fokt, Izabela / Szymanski, Slawomir / Skora, Stanislaw / Szeja, Wiesław / Grynkiewicz, Grzegorz / Lesyng, Bogdan / Priebe, Waldemar / Kaminska, Bozena

    Cancer biology & therapy

    2012  Volume 13, Issue 8, Page(s) 657–670

    Abstract: JAK (Janus kinase)/STAT (signal transducers and activators of transcription) signaling is involved in the regulation of cell growth, differentiation and apoptosis. Constitutive activation of STATs, in particular STAT3, is observed in a large number of ... ...

    Abstract JAK (Janus kinase)/STAT (signal transducers and activators of transcription) signaling is involved in the regulation of cell growth, differentiation and apoptosis. Constitutive activation of STATs, in particular STAT3, is observed in a large number of human tumors, including gliomas and may contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis, thus it emerges as a promising target for anti-cancer therapy. To investigate the therapeutic potential of blocking STAT3 in glioma cells a set of small synthetic molecules - caffeic acid derivatives, structurally related to AG490 was screened for its ability to inhibit STAT3. Inhibitor 2 (E)-2-cyano-N-[(S)-1-phenylethyl]-3-(pyridin-2-yl)acrylamide was the most effective in inhibition of JAK/STAT3 signaling and at doses ≥ 25 μM significantly reduced the level of phosphorylated JAK1, JAK2 and STAT3 (at Tyr705) and downregulated the expression of known STAT3 targets. In treated cells we observed rapid detachment and rounding of cells associated with reduction of focal adhesion kinase phosphorylation and activity, followed by upregulation of phosphorylated p38, JNK and ERK1/2 levels. Accumulation of cells with fragmented DNA, increases of the cleaved caspase 3 and fragmented PARP levels were detected 24 h after the treatment suggesting ongoing apoptotic cell death. Three human malignant glioblastoma cell lines defective in tumor suppressors TP53 and/or PTEN were susceptible to inhibitor 2 that induced the programmed cell death. Global gene expression profiling revealed modulation of numerous genes in cells treated with inhibitor 2 revealing novel, potential JAK/STAT targets. Our study demonstrates that suitably modified caffeic acid molecules exhibit significant cytotoxic potential toward glioma cells.
    MeSH term(s) Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/toxicity ; Apoptosis/drug effects ; Cell Line, Tumor ; Cluster Analysis ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Glioma/genetics ; Glioma/metabolism ; Humans ; Janus Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation/drug effects ; Rats ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Tyrphostins/chemistry ; Tyrphostins/pharmacology ; Tyrphostins/toxicity
    Chemical Substances Antineoplastic Agents ; STAT3 Transcription Factor ; Tyrphostins ; alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide ; Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2) ; Janus Kinases (EC 2.7.10.2) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2012-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2146305-0
    ISSN 1555-8576 ; 1538-4047
    ISSN (online) 1555-8576
    ISSN 1538-4047
    DOI 10.4161/cbt.20083
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5887: Show issues Location:
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