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Dependent Signaling (dependent + signaling)

Distribution by Scientific Domains
Medical Sciences80%

Terms modified by Dependent Signaling

  • dependent signaling pathway
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    Selected Abstracts

    Real-time observation of Wnt ,-catenin signaling in the chick embryo

    DEVELOPMENTAL DYNAMICS, Issue 1 2010
    Anne C. Rios
    Abstract A critical mediator of cell,cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Reporter constructs containing multimerized TCF DNA binding sites have been used to detect Wnt ,-catenin dependent activity during animal development. In this report, we have constructed and compared several TCF green fluorescent protein (GFP) reporter constructs. They contained 3, 8, or 12 TCF binding sites upstream of a minimal promoter driving native or destabilized enhanced GFP (EGFP). We have used the electroporation of somites in the chick embryo as a paradigm to test them in vivo. We have verified that they all respond to Wnt signaling in vivo. We have then assessed their efficiency at reflecting the activity of the Wnt pathway. Using destabilized EGFP reporter constructs, we show that somite cells dynamically regulate Wnt/,-catenin,dependent signaling, a finding that was confirmed by performing time-lapse video confocal observation of electroporated embryos. Developmental Dynamics 239:346,353, 2010. © 2009 Wiley-Liss, Inc. [source]

    CNTO 859, a humanized anti-tissue factor monoclonal antibody, is a potent inhibitor of breast cancer metastasis and tumor growth in xenograft models

    INTERNATIONAL JOURNAL OF CANCER, Issue 6 2007
    Cam V. Ngo
    Abstract Thromboembolic complications are frequently associated with advanced cancer. Interestingly, one of the major initiators of blood coagulation, tissue factor (TF), is reported to be overexpressed in several tumor types and can be found on both tumor cells and tumor vasculature. Although the exact mechanisms have yet to be elucidated, TF expressed on tumor cells can trigger intracellular signaling events through various pathways that can lead to tumor angiogenesis, proliferation, and metastasis. There exists preclinical evidence that disruption of TF dependent signaling can effectively inhibit tumor cell migration, metastasis, and angiogenesis. Here, we report for the first time that an antibody to tissue factor can also prevent tumor growth in vivo. Prophylactic administration of CNTO 859, a humanized anti-human TF antibody, was shown to inhibit experimental lung metastasis of MDA-MB-231 human breast carcinoma cells by over 99% compared to a control antibody. Furthermore, therapeutic doses of CNTO 859 were shown to reduce tumor incidence and growth of orthotopically implanted MDA-MB-231 cells. © 2006 Wiley-Liss, Inc. [source]

    Chondrocyte innate immune myeloid differentiation factor 88,dependent signaling drives procatabolic effects of the endogenous toll-like receptor 2/toll-like receptor 4 ligands low molecular weight hyaluronan and high mobility group box chromosomal protein 1 in mice

    ARTHRITIS & RHEUMATISM, Issue 7 2010
    Ru Liu-Bryan
    Objective Toll-like receptor 2 (TLR-2)/TLR-4,mediated innate immunity serves as a frontline antimicrobial host defense, but also modulates tissue remodeling and repair responses to endogenous ligands released during low-grade inflammation. We undertook the present study to assess whether the endogenous TLR-2/TLR-4 ligands low molecular weight hyaluronan (LMW-HA) and high mobility group box chromosomal protein 1 (HMGB-1), which are increased in osteoarthritic (OA) joints, drive procatabolic chondrocyte responses dependent on TLR-2 and TLR-4 signaling through the cytosolic adaptor myeloid differentiation factor 88 (MyD88). Methods We studied mature femoral head cap cartilage explants and immature primary knee articular chondrocytes from TLR-2/TLR-4,double-knockout, MyD88-knockout, and congenic wild-type mice. Generation of nitric oxide (NO), degradation of hyaluronan, release of HMGB-1, matrix metalloproteinase 3 (MMP-3), and MMP-13, and protein expression of type X collagen were assessed by Griess reaction and Western blotting analyses. Expression of messenger RNA for type II and type X collagen, MMP-13, and RUNX-2 was examined by real-time quantitative reverse transcription,polymerase chain reaction. Results Interleukin-1, and TLR-2 and TLR-4 ligands induced both HMGB-1 release from chondrocytes and extracellular LMW-HA generation in normal chondrocytes. TLR-2/TLR-4,/, and MyD88,/, mouse cartilage explants and chondrocytes lost the capacity to mount procatabolic responses to both LMW-HA and HMGB-1, demonstrated by >95% suppression of NO production (P < 0.01), and attenuated induction of MMP-3 and MMP-13. Combined deficiency of TLR-2/TLR-4, or of MyD88 alone, also attenuated release of NO and blunted induction of MMP-3 and MMP-13 release. MyD88 was necessary for HMGB-1 and hyaluronidase 2 (which generates LMW-HA) to induce chondrocyte hypertrophy, which is implicated in OA progression. Conclusion MyD88-dependent TLR-2/TLR-4 signaling is essential for procatabolic responses to LMW-HA and HMGB-1, and MyD88 drives chondrocyte hypertrophy. Therefore, LMW-HA and HMGB-1 act as innate immune cytokine-like signals with the potential to modulate chondrocyte differentiation and function in OA progression. [source]

    Endothelin 1 contributes to the effect of transforming growth factor ,1 on wound repair and skin fibrosis

    ARTHRITIS & RHEUMATISM, Issue 3 2010
    David Lagares
    Objective To characterize the pathways induced by transforming growth factor ,1 (TGF,1) that lead to the expression of endothelin 1 (ET-1) in human dermal fibroblasts, and to study the effects of TGF,1 and ET-1 on the acquisition of a profibrotic phenotype and assess the contribution of the TGF,1/ET-1 axis to skin wound healing and fibrosis in vivo. Methods The mechanism of induction of ET-1 expression by TGF,1 and its effect on the expression of ,-smooth muscle actin and type I collagen were studied in human dermal fibroblasts, in experiments involving the TGF, receptor inhibitor GW788388 and the ET receptor antagonist bosentan, by real-time reverse transcription,polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay, immunofluorescence, Western blotting, and promoter/reporter transient transfection analyses. Experiments assessing dermal wound healing in mice were performed with adenovirus-driven overexpression of active TGF,1 and ET-1, with or without treatment with bosentan. The contributions of TGF,1 and ET-1 to the fibrotic response were also assessed in a mouse model of bleomycin-induced skin fibrosis, by histologic, immunohistochemical, RT-PCR, and protein analyses. Results TGF,1 induced ET-1 expression in human dermal fibroblasts through Smad- and activator protein 1/JNK,dependent signaling. The ability of TGF,1 to induce the expression of profibrotic genes was dependent on ET-1. Adenovirus-mediated overexpression of TGF,1 and ET-1 in mouse skin was associated with accelerated wound closure, increased fibrogenesis, and excessive scarring. Treatment with bosentan prevented the effects of TGF,1. In the bleomycin-induced fibrosis model, treatment with GW788388 and bosentan prevented the fibrotic response. Conclusion Our results strongly support the notion that the TGF,1/ET-1 axis has a role in wound repair and skin fibrosis. ET-1 receptor antagonists, such as bosentan, may represent a useful therapeutic tool in the treatment of excessive scarring and fibrosis-related diseases. [source]

    An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus

    ARTHRITIS & RHEUMATISM, Issue 5 2008
    Frances Rena Bahjat
    Objective To assess whether R788, an orally bioavailable small molecule inhibitor of spleen tyrosine kinase (Syk),dependent signaling, could modulate disease in lupus-prone (NZB × NZW)F1 (NZB/NZW) mice via inhibition of Fc receptor (FcR) and B cell receptor signaling. Methods R788 was administered to NZB/NZW mice before and after disease onset. Proteinuria, blood urea nitrogen levels, and autoantibody titers were examined periodically, and overall survival and renal pathologic features were assessed following long-term treatment (24,34 weeks). The distribution and immunophenotype of various splenic T cell and B cell subpopulations were evaluated at the time of study termination. Arthus responses in NZB/NZW mice pretreated with R788 or Fc-blocking antibody (anti-CD16/32) were also examined. Results When R788 was administered prior to or after disease onset, it delayed the onset of proteinuria and azotemia, reduced renal pathology and kidney infiltrates, and significantly prolonged survival of lupus-prone NZB/NZW mice; autoantibody titers were minimally affected throughout the study. Dose-dependent reductions in the numbers of CD4+ activated T cells expressing high levels of CD44 or CD69 were apparent in spleens from R788-treated mice. Minimal effects on the numbers of naive T cells expressing CD62 ligand and total CD8+ T cells per spleen were observed following long-term drug treatment. R788 pretreatment resulted in reduced Arthus responses in NZB/NZW mice, similar to results obtained in mice pretreated with FcR-blocking antibody. Conclusion We demonstrate that a novel Syk-selective inhibitor prevents the development of renal disease and treats established murine lupus nephritis. These data suggest that Syk inhibitors may be of therapeutic benefit in human lupus and related disorders. [source]