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JAK/STAT Pathway (jak + pathway)
Selected AbstractsActivation of the JAK/STAT Pathway in Epstein Barr Virus+ -Associated Posttransplant Lymphoproliferative Disease: Role of Interferon-,AMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009M. Vaysberg Epstein Barr virus (EBV) is associated with B-cell lymphomas in posttransplant lymphoproliferative disease (PTLD). Latent membrane protein 1 (LMP1), the major oncogenic protein of EBV, promotes tumorigenesis through activation of NF-,B, Erk, p38, JNK and Akt. The Jak/STAT signal transduction pathway is also constitutively active in PTLD-associated EBV+ B-cell lymphomas. Here we determine the mechanism of Jak/STAT activation in EBV+ B-cell lymphomas and the role of LMP1 in this process. Immunoprecipitation studies revealed no direct interaction of LMP1 and JAK3, but known associations between JAK3 and common gamma chain, and between LMP1 and TRAF3, were readily detected in EBV+ B cell lines from patients with PTLD. An inducible LMP1 molecule expressed in EBV, BL41 Burkitt's cells demonstrated STAT activation only after prolonged LMP1 signaling. While LMP1 induced IFN-, production in BL41 cells, IFN-, receptor blockade and IFN-, neutralization prior to LMP1 activation markedly decreased STAT1 activation and expression of LMP1-driven IFN-, inducible genes. Understanding the mechanisms by which EBV induces cellular signal transduction pathways may facilitate development of new treatments for PTLD. [source] S14-95, a Novel Inhibitor of the JAK/STAT Pathway from a Penicillium Species.CHEMINFORM, Issue 41 2003Gerhard Erkel Abstract For Abstract see ChemInform Abstract in Full Text. [source] Genome-wide expression profiling in the Drosophila eye reveals unexpected repression of notch signaling by the JAK/STAT pathwayDEVELOPMENTAL DYNAMICS, Issue 9 2009Maria Sol Flaherty Abstract Although the JAK/STAT pathway regulates numerous processes in vertebrates and invertebrates through modulating transcription, its functionally relevant transcriptional targets remain largely unknown. With one jak and one stat (stat92E), Drosophila provides a powerful system for finding new JAK/STAT target genes. Genome-wide expression profiling on eye discs in which Stat92E is hyperactivated, revealed 584 differentially regulated genes, including known targets domeless, socs36E, and wingless. Other differentially regulated genes (chinmo, lama, Mo25, Imp-L2, Serrate, Delta) were validated and may represent new Stat92E targets. Genetic experiments revealed that Stat92E cell-autonomously represses Serrate, which encodes a Notch ligand. Loss of Stat92E led to de-repression of Serrate in the dorsal eye, resulting in ectopic Notch signaling and aberrant eye growth there. Thus, our micro-array documents a new Stat92E target gene and a previously unidentified inhibitory action of Stat92E on Notch signaling. These data suggest that this study will be a useful resource for the identification of additional Stat92E targets. Developmental Dynamics 238:2235,2253, 2009. © 2009 Wiley-Liss, Inc. [source] The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2004Patricia Gomez-Bougie Abstract Multiple myeloma is a fatal B,cell malignancy characterized by the accumulation of plasma cells within the bone marrow. IL-6 is a major survival factor for myeloma cells. Bcl-2 protein family regulates pathways to apoptosis that are activated upon growth factor deprivation. Pro-apoptotic proteins that have only a single Bcl-2 homology domain, BH3-only, are potent inducers of apoptosis. In myeloma cells, Mcl-1 has been shown to be a major anti-apoptotic protein that appears to regulate cell survival through the JAK/STAT pathway. In this study, we examined the regulation of the BH3-only protein Bim and its interaction with Mcl-1. The three major Bim isoforms are expressed in myeloma cells and are negatively regulated by IL-6. Blockade of IL-6 signaling induces an up-regulation of Bim concomitant to Mcl-1 down-regulation. Of major interest, Bim is found strongly associated with Mcl-1 in viable myeloma cells while this interaction is disrupted under apoptosis induction. Of note, while Bim is also found strongly associated to Bcl-2, this interaction is not changed under apoptosis induction. Thus, in myeloma cells, Mcl-1 neutralizes Bim through complex formation and therefore prevents apoptosis. Under apoptosis induction, the disappearance of Mcl-1 allows Bim to exercise its pro-apoptotic function and to activate Bax. [source] TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2010Vijay Ramakrishnan Interaction of myeloma cells with the bone marrow microenvironment is mediated in large part through different cytokines, especially VEGF and IL6. These cytokines, especially IL6, leads to upregulation of the JAK/STAT pathway in myeloma cell, contributing to increased proliferation, decreased apoptosis, and acquired drug resistance. Here, we examined the preclinical activity of a novel JAK2 inhibitor TG101209. TG101209 induced dose- and time-dependent cytotoxicity in a variety of multiple myeloma (MM) cell lines. The induction of cytotoxicity was associated with inhibition of cell cycle progression and induction of apoptosis in myeloma cell lines and patient-derived plasma cells. Evaluation of U266 cell lines and patient cells, which have a mix of CD45 positive and negative cells, demonstrated more profound cytotoxicity and antiproliferative activity of the drug on the CD45+ population relative to the CD45, cells. Exploring the mechanism of action of TG101209 indicated downregulation of pJak2, pStat3, and Bcl-xl levels with upregulation of pErk and pAkt levels indicating cross talk between signaling pathways. TG101209, when used in combination with the PI3K inhibitor LY294002, demonstrated synergistic cytotoxicity against myeloma cells. Our results provide the rationale for clinical evaluation of TG101209 alone or in combination with PI3K/Akt inhibitors in MM. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Interleukin-7 stimulates secretion of S100A4 by activating the JAK/STAT signaling pathway in human articular chondrocytesARTHRITIS & RHEUMATISM, Issue 3 2009Raghunatha R. Yammani Objective S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. Methods Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1, (IL-1,), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. Results Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1,. IL-7 activated the JAK/STAT pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7,mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7,mediated secretion of S100A4, but pretreatment with brefeldin A did not. Conclusion IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this signaling pathway could contribute to cartilage destruction during the development of OA. [source] Insulin-like growth factor-I receptor signal transduction and the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathwayBIOFACTORS, Issue 1 2009Eddy Himpe Abstract The insulin-like growth factor IGF-I is an important fetal and postnatal growth factor, which is also involved in tissue homeostasis via regulation of proliferation, differentiation, and cell survival. To understand the role of IGF-I in the pathophysiology of a variety of disorders, including growth disorders, cancer, and neurodegenerative diseases, a detailed knowledge of IGF-I signal transduction is required. This knowledge may also contribute to the development of new therapies directed at the IGF-I receptor or other signaling molecules. In this review, we will address IGF-I receptor signaling through the JAK/STAT pathway in IGF-I signaling and the role of cytokine-induced inhibitors of signaling (CIS) and suppressors of cytokine signaling (SOCS). It appears that, in addition to the canonical IGF-I signaling pathways through extracellular-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K)-Akt, IGF-I also signals through the JAK/STAT pathway. Activation of this pathway may lead to induction of SOCS molecules, well-known feedback inhibitors of the JAK/STAT pathway, which also suppress of IGF-I-induced JAK/STAT signaling. Furthermore, other IGF-I-induced signaling pathways may also be modulated by SOCS. It is conceivable that the effect of these classical inhibitors of cytokine signaling directly affect IGF-I receptor signaling, because they are able to associate to the intracellular part of the IGF-I receptor. These observations indicate that CIS and SOCS molecules are key to cross-talk between IGF-I receptor signaling and signaling through receptors belonging to the hematopoietic/cytokine receptor superfamily. Theoretically, dysregulation of CIS or SOCS may affect IGF-I-mediated effects on body growth, cell differentiation, proliferation, and cell survival. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] Cantharidin induces apoptosis of human multiple myeloma cells via inhibition of the JAK/STAT pathwayCANCER SCIENCE, Issue 9 2008Morihiko Sagawa Multiple myeloma is an incurable B-cell malignancy requiring new therapeutic strategies in clinical settings. Interleukin (IL),6 signaling pathways play a critical role in the pathogenesis of multiple myeloma. The traditional Chinese medicine cantharidin (CTD) has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of CTD as a novel therapeutic agent for the patients with multiple myeloma. We investigated the in vitro effects of CTD for its antimyeloma activity, and further examined the molecular mechanisms of CTD-induced apoptosis. CTD inhibited the cellular growth of human myeloma cell lines as well as freshly isolated myeloma cells in patients. Cultivation with CTD induced apoptosis of myeloma cells in a cell-cycle-independent manner. Treatment with CTD induced caspase-3, ,8, and ,9 activities, and it was completely blocked by each caspase inhibitor. We further examined the effect of CTD on the IL-6 signaling pathway in myeloma cells, and found that CTD inhibited phosphorylation of STAT3 at tyrosine 705 residue as early as 1 h after treatment and down-regulated the expression of the antiapoptotic bcl-xL protein. STAT3 directly bound and activated the transcription of bcl-xL gene promoter, resulting in the induction of the expression of bcl-xL in myeloma cells. The essential role of STAT3 in CTD effects was confirmed by transfection with the constitutively active and dominant negative form of STAT3 in U266 cells. In conclusion, we have demonstrated that CTD is a promising candidate to be a new therapeutic agent in signal transduction therapy. (Cancer Sci 2008; 99: 1820,1826) [source] Signaling events leading to the curative effect of cystatin on experimental visceral leishmaniasis: Involvement of ERK1/2, NF-,B and JAK/STAT pathwaysEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2009Susanta Kar Abstract Curative effect of cystatin, a natural cystein protease inhibitor, on experimental visceral leishmaniasis was associated with strong upregulation of iNOS. The transductional mechanisms underlying this cellular response was investigated in the murine macrophage cell line RAW 264.7 and in the BALB/c mouse model of visceral leishmaniasis. Cystatin synergizes with IFN-, in inducing ERK1/2 phosphorylation and NF-,B DNA-binding activity. Pretreatment of cells with specific inhibitors of NF-,B or ERK1/2 pathway blocked the cystatin plus IFN-,-inducible NF-,B activity and markedly reduced the expression of iNOS at both mRNA and protein levels. Silencing of mitogen- and stress-activated protein kinase 1 significantly reduced cystatin-mediated NF-,B-dependent iNOS gene transcription suggesting the involvement of mitogen- and stress-activated protein kinase 1 activation in ERK1/2 signaling. DNA binding as well as silencing experiments revealed the requirement of IFN-,-mediated JAK-STAT activation even though cystatin did not modulate this signaling cascade by itself. In the in vivo situation, key steps in the activation cascade of NF-,B, including nuclear translocation of NF-,B subunits, I,B phosphorylation and I,B kinase, are all remarkably enhanced in Leishmania -infected mice by cystatin. Understanding the molecular mechanisms through which cystatin modulates macrophage effector responses will contribute to better define its potential for macrophage-associated diseases, in general. [source] Interleukin-6-induced proliferation of pre-B cells mediated by receptor complexes lacking the SHP2/SOCS3 recruitment sites revisitedFEBS JOURNAL, Issue 24 2001Kerstin Friederichs Interleukin-6 (IL-6) induces B-cell proliferation by binding to receptor complexes composed of a specific ,-receptor (gp80; CD126) and the signal transducing receptor subunit gp130 (CD130). Immediately after receptor complex activation, signal transducers and activators of transcription (STATs) 1 and 3 and the Src-homology domain-containing protein tyrosine phosphatase 2 (SHP2) are recruited to gp130 and subsequently tyrosine phosphorylated. The activated dimerized STATs translocate to the nucleus and bind to enhancer elements of IL-6-inducible genes. SHP2 acts as an adapter and links the Jak/STAT pathway to the Ras/Raf/MAPK cascade but it is also involved in signal attenuation. Whereas STAT3 activation appears to be crucial for all biological activities of IL-6, the requirement of SHP2-activation depends on the individual biological response analyzed. The requirement of SHP2 activation for the pre-B cell (Ba/F3) proliferation has been reported previously [Fukada, T., Hibi, M., Yamanaka, Y., Takahashi-Tezuka, M., Fujitani, Y., Yamaguchi, T., Nakajima, K. & Hirano, T. (1996) Immunity5, 449,460]. In contrast, we have recently demonstrated that the presence of a single STAT-recruitment site within gp130 is sufficient for IL-6- induced proliferation of Ba/F3 cells [Schmitz, J., Dahmen, H., Grimm, C., Gendo, C., Müller-Newen, G., Heinrich, P.C. & Schaper, F. (2000) J. Immunol.164, 848,854]. To unravel this discrepancy we analyzed the IL-6-induced dose-dependent proliferation of Ba/F3 cells mediated by receptor complexes lacking SHP2/SOCS3 recruitment sites. Surprisingly, pre-B cells, after stimulation with low amounts of IL-6, proliferate much more efficiently in the absence of the activated SHP2 than in the presence of the tyrosine phosphatase. Therefore, SHP2 activation appears to be relevant for IL-6-induced proliferation only after stimulation with very large amounts of IL-6. [source] PIBF: The Double Edged Sword.AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2010Pregnancy, Tumor Citation Szekeres-Bartho J, Polgar B. PIBF: The Double Edged Sword. Pregnancy and Tumor. Am J Reprod Immunol 2010; 64: 77,86 Problem, The role of progesterone-dependent immunomodulation in the maintenance of normal pregnancy. Methods,In vitro and in vivo data on the effect that progesterone and its mediator progesterone-induced blocking factor (PIBF) exert on the immune functions of pregnant women are reviewed, together with clinical findings. Results, Activated pregnancy lymphocytes express progesterone receptors, which enable progesterone to induce a protein called PIBF. PIBF increases Th2 type cytokine production by signaling via a novel type of IL-4 receptor and activating the Jak/STAT pathway. PIBF inhibits phosholipase A2, thus reduces prostaglandin synthesis. PIBF inhibits perforin release in human decidual lymphocytes and reduces the deleterious effect of high NK activity on murine pregnancy. PIBF production is a characteristic feature of normal human pregnancy, and its concentration is reduced in threatened pregnancies. PIBF mRNA and protein are expressed in a variety of malignant tumors. Inhibition of PIBF synthesis increases survival rates of leukemic mice. Conclusion, Progesterone-induced blocking factor is produced by pregnancy lymphocytes and also by malignant tumors. The PIBF-induced Th2-dominant immune response is favorable during pregnancy but might facilitate tumor growth by suppressing local antitumor immune responses. [source] Influenza A virus abrogates IFN-, response in respiratory epithelial cells by disruption of the Jak/Stat pathwayEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2008Kohsaku Uetani Abstract The innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-, is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-, as evidenced by studies using anti-IFN-, Ab and IFN-,,/, mice. Thus, we hypothesized that IFN-, is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-,. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-, to detect IFN-,-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-,-induced up-regulation of HLA-DR, mRNA and the IFN-, induction of class II transactivator (CIITA), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1, upon IFN-, stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1,. Thus, influenza A virus subverts antiviral host defense mediated by IFN-, through effects on the intracellular signaling pathways. [source] | ||||||||||||||||