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  • Cation exchange chromatography in antibody purification: pH screening for optimised binding and HCP removal. 17113367

    The production of pharmaceutical antibodies requires reliable and rapid processes with high purity and yield. Although protein A gels selectively and efficiently bind antibodies in the capture step, intense research is going on to find alternatives that can abolish the drawbacks of protein A chromatography. Ion exchangers e.g. are more robust, considerably cheaper and can eliminate ligand leaching. For the strong cation exchangers Fractogel EMD SO3- (M) and Fractogel EMD SE Hicap (M) we have evaluated the influence of pH for optimised binding and removal of host cell protein (HCP). In a fast initial screening we measured batch binding capacities. Subsequent scale-down to 96-well plate format proved that assay miniaturisation still provided reliable data. We demonstrated with the principle of residence time that scout columns are suitable for dynamic studies. The optimum pH range from batch binding was transferred to scout columns which were then used to screen for maximum dynamic capacities. In addition IEF titration curve analysis was employed to define a final operational pH. With this pH we ran labscale columns to purify monoclonal antibody. The cation exchangers showed high step yields and host cell proteins in the pools from gradient elution were reduced very effectively.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    16-200
    Produktbezeichnung:
    Anti-Histidine Tagged Antibody, clone 4D11, biotin conjugate

  • SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α. 29422508

    One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme usually repressed in the tumor milieu. Here we show that specific SOD3 re-expression in tumor-associated endothelial cells (ECs) increases doxorubicin (Doxo) delivery into and chemotherapeutic effect on tumors. Enhanced SOD3 activity fostered perivascular nitric oxide accumulation and reduced vessel leakage by inducing vascular endothelial cadherin (VEC) transcription. SOD3 reduced HIF prolyl hydroxylase domain protein activity, which increased hypoxia-inducible factor-2α (HIF-2α) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2α ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2α levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    17-371
    Produktbezeichnung:
    EZ-ChIP™

  • SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. 21590492

    The suppressor of cytokine signaling 3 (SOCS3) gene is one of eight structurally related genes of the SOCS family and has been suggested to function as a tumor suppressor by inhibition of the JAK/STAT signaling pathway. We investigated 60 human gliomas of different histological types for SOCS3 alterations and found frequent SOCS3 promoter hypermethylation and transcriptional downregulation. However, SOCS3 promoter hypermethylation was virtually absent in primary glioblastomas, which are characterized by frequent epidermal growth factor receptor (EGFR) amplification and overexpression. Assessment of the relationship between SOCS3 and EGFR aberrations revealed that SOCS3 promoter hypermethylation was inversely related to both the EGFR gene dosage as well as the EGFR protein expression, thus suggesting SOCS3 inactivation as a mechanism substituting for EGFR activation in a subset of gliomas. In support of this hypothesis, stable shRNA-mediated SOCS3 knock-down in U251 glioblastoma cells resulted in an activation of EGFR-related signaling pathways, i.e. an increase in the activation levels of STAT3, FAK and to a lesser extent MAPK, while the AKT phosphorylation levels remained unaffected. Functionally, SOCS3-depletion caused strongly increased tumor cell invasion with no obvious effect on tumor cell proliferation. In summary, our findings suggest that SOCS3 inactivation by promoter hypermethylation is mutually exclusive to EGFR activation in gliomas and preferentially promotes glioma cell invasion through STAT3 and FAK activation.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    S7821
    Produktbezeichnung:
    CpGenome Universal Methylated DNA

  • Overexpression of SOCS3 inhibits astrogliogenesis and promotes maintenance of neural stem cells. 16805839

    To investigate the effects of suppressors of cytokine signaling 3 (SOCS3) on neural stem cell fate, stem cells were infected with an adenoviral vector expressing SOCS3. Three days later, western blot analysis and immunocytochemical analysis revealed that the protein level of MAP2 and the number of MAP2-positive cells were significantly increased in SOCS3-transfected cells, whereas the protein level of GFAP and the number of GFAP-positive cells were significantly decreased. Furthermore, promoter assay revealed a significant reduction in the transcriptional level of signal transducer and activator of transcription 3 (Stat3) in the transfected cells. In addition, the mRNA levels of Notch family member (notch1) and inhibitory basic helix-loop-helix (bHLH) factors (hes5 and id3) were significantly up-regulated 1 day after overexpression of SOCS3. Three days after transfection, the mRNA level of hes5 was significantly decreased, whereas that of notch1 was still up-regulated. Moreover, all of SOCS3-positive cells expressed Nestin protein but did not express MAP2 or GFAP proteins. These data indicate that overexpression of SOCS3 induced neurogenesis and inhibited astrogliogenesis in neural stem cells. Our data also show that SOCS3 promoted maintenance of neural stem cells.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    MAB353
    Produktbezeichnung:
    Anti-Nestin Antibody, clone rat-401

  • Interaction between Hhex and SOX13 Modulates Wnt/TCF Activity. 20028982

    Fine-tuning of the Wnt/TCF pathway is crucial for multiple embryological processes, including liver development. Here we describe how the interaction between Hhex (hematopoietically expressed homeobox) and SOX13 (SRY-related high mobility group box transcription factor 13), modulates Wnt/TCF pathway activity. Hhex is a homeodomain factor expressed in multiple endoderm-derived tissues, like the liver, where it is essential for proper development. The pleiotropic expression of Hhex during embryonic development and its dual role as a transcriptional repressor and activator suggest the presence of different tissue-specific partners capable of modulating its activity and function. While searching for developmentally regulated Hhex partners, we set up a yeast two-hybrid screening using an E9.5-10.5 mouse embryo library and the N-terminal domain of Hhex as bait. Among the putative protein interactors, we selected SOX13 for further characterization. We found that SOX13 interacts directly with full-length Hhex, and we delineated the interaction domains within the two proteins. SOX13 is known to repress Wnt/TCF signaling by interacting with TCF1. We show that Hhex is able to block the SOX13-dependent repression of Wnt/TCF activity by displacing SOX13 from the SOX13.TCF1 complex. Moreover, Hhex de-repressed the Wnt/TCF pathway in the ventral foregut endoderm of cultured mouse embryos electroporated with a SOX13-expressing plasmid. We conclude that the interaction between Hhex and SOX13 may contribute to control Wnt/TCF signaling in the early embryo.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    16-201
    Produktbezeichnung:
    Protein G Agarose/Salmon Sperm DNA, 2.5 mL

  • Insulin receptor and IRS-1 co-immunoprecipitation with SOCS-3, and IKKα/β phosphorylation are increased in obese Zucker rat skeletal muscle. 22982470

    We evaluated if selected pro-inflammatory cytokines and/or the protein suppressor of cytokine signaling 3 (SOCS-3) could account for decreased insulin-stimulated phosphatidylinositol 3-kinase (PI3-K) activity in the skeletal muscle of the obese Zucker rat.Eight lean and eight obese Zucker rats ~4weeks of age were obtained and allowed to feed ad libitum for 4weeks before undergoing hind limb perfusion in the presence of 500μU/ml insulin.Insulin-stimulated skeletal muscle PI3-K activity and 3-O-methylglucose transport rates were reduced (Pless than 0.05) in obese compared to lean animals. IRS-1 concentration remained unchanged although IRS-1 tyrosine phosphorylation was decreased (Pless than 0.05), and IRS-1 serine phosphorylation (pS) was increased (Pless than 0.05) in obese animals compared to lean animals. IKKα/β pS and JNK theronine/tyrosine phosphorylation was increased (Pless than 0.05) in the obese animals. IκBα concentration was decreased (Pless than 0.05) and IκBα pS was increased (Pless than 0.05) in the obese compared to lean Zucker animals. SOCS-3 concentration and SOCS-3 co-immunoprecipitation with both insulin receptor β-subunit (IR-β) and IRS-1 were elevated (Pless than 0.05) in obese compared to lean animals. IRS-1 co-immunoprecipitation with IR-β was reduced 56% in the obese animals.Increased IKKα/β and JNK serine phosphorylation may contribute to increasing IRS-1 serine phosphorylation, while concurrent co-localization of SOCS-3 with both IR-β and IRS-1 may prevent IRS-1 from interacting with IR-β. These two mechanisms thusly may independently contribute to impairing insulin-stimulated PI3-K activation in the skeletal muscle of the obese Zucker rat.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    Mehrere
    Produktbezeichnung:
    Mehrere

  • High-fat feeding increases insulin receptor and IRS-1 coimmunoprecipitation with SOCS-3, IKKalpha/beta phosphorylation and decreases PI-3 kinase activity in muscle. 19386987

    Suppressor of cytokine signaling (SOCS) proteins and/or activation of the proinflammatory pathway have been postulated as possible mechanisms that may contribute to skeletal muscle insulin resistance. Thus, the aims of the present investigation were to determine in high-fat-fed skeletal muscle: 1) whether SOCS-3 protein concentration is increased, 2) whether coimmunoprecipitation of SOCS-3 with the insulin receptor-beta subunit and/or IRS-1 is increased, and 3) whether select components of the proinflammatory pathway are altered. Thirty-two male Sprague-Dawley rats were assigned to either control (CON, n = 16) or high-fat-fed (HF, n = 16) dietary groups for 12 wk and then subjected to hind limb perfusions in the presence (n = 8/group) or absence (n = 8/group) of insulin. Insulin-stimulated skeletal muscle 3-MG transport rates and PI-3 kinase activity were greater (P less than 0.05) in CON. IRS-1 tyrosine phosphorylation was decreased (P less than 0.05), and IRS-1 serine 307 phosphorylation was increased (P less than 0.05) in HF. Insulin receptor-beta (IR-beta) subunit coimmunoprecipitation with IRS-1 was reduced in HF. SOCS-3 protein concentration and SOCS-3 coimmunoprecipitation with both the IR-beta subunit and IRS-1 was increased (P less than 0.05) in HF. IKKalpha/beta serine phosphorylation was increased (P less than 0.05), IkappaBalpha protein concentration was decreased (P less than 0.05) and IkappaBalpha serine phosphorylation was increased (P less than 0.05) in HF. Increased colocalization of SOCS-3 with both the IR-beta subunit and IRS-1 may provide steric hindrance that prevents IRS-1 from interacting with IR-beta, while increased IKKbeta serine phosphorylation may contribute to increasing IRS-1 serine phosphorylation, both of which independently can have deleterious effects on insulin-stimulated PI-3 kinase activation in high-fat-fed rodent skeletal muscle.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    Mehrere
    Produktbezeichnung:
    Mehrere

  • Early postnatal hyperalimentation impairs renal function via SOCS-3 mediated renal postreceptor leptin resistance. 22253420

    Early postnatal hyperalimentation has long-term implications for obesity and developing renal disease. Suppressor of cytokine signaling (SOCS) 3 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and ERK1/2 and thereby plays a pivotal role in mediating leptin resistance. In addition, SOCS-3 is induced by both leptin and inflammatory cytokines. However, little is known about the intrinsic-renal leptin synthesis and function. Therefore, this study aimed to elucidate the implications of early postnatal hyperalimentation on renal function and on the intrinsic-renal leptin signaling. Early postnatal hyperalimentation in Wistar rats during lactation was induced by litter size reduction at birth (LSR) either to LSR10 or LSR6, compared with home cage control male rats. Assessment of renal function at postnatal day 70 revealed decreased glomerular filtration rate and proteinuria after LSR6. In line with this impairment of renal function, renal inflammation and expression as well as deposition of extracellular matrix molecules, such as collagen I, were increased. Furthermore, renal expression of leptin and IL-6 was up-regulated subsequent to LSR6. Interestingly, the phosphorylation of Stat3 and ERK1/2 in the kidney, however, was decreased after LSR6, indicating postreceptor leptin resistance. In accordance, neuropeptide Y (NPY) gene expression was down-regulated; moreover, SOCS-3 protein expression, a mediator of postreceptor leptin resistance, was strongly elevated and colocalized with NPY. Thus, our findings not only demonstrate impaired renal function and profibrotic processes but also provide compelling evidence of a SOCS-3-mediated intrinsic renal leptin resistance and concomitant up-regulated NPY expression as an underlying mechanism.
    Dokumententyp:
    Referenz
    Produkbestellnummer:
    AB1296