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  • Expression of the homeobox gene HOXA9 in ovarian cancer induces peritoneal macrophages to acquire an M2 tumor-promoting phenotype. 24332016

    Tumor-associated macrophages (TAMs) exhibit an M2 macrophage phenotype that suppresses anti-tumor immune responses and often correlates with poor outcomes in patients with cancer. Patients with ovarian cancer frequently present with peritoneal carcinomatosis, but the mechanisms that induce naïve peritoneal macrophages into TAMs are poorly understood. In this study, we found an increased abundance of TAMs in mouse i.p. xenograft models of ovarian cancer that expressed HOXA9, a homeobox gene that is associated with poor prognosis in patients with ovarian cancer. HOXA9 expression in ovarian cancer cells stimulated chemotaxis of peritoneal macrophages and induced macrophages to acquire TAM-like features. These features included induction of the M2 markers, CD163 and CD206, and the immunosuppressive cytokines, IL-10 and chemokine ligand 17, and down-regulation of the immunostimulatory cytokine, IL-12. HOXA9-mediated induction of TAMs was primarily due to the combinatorial effects of HOXA9-induced, tumor-derived transforming growth factor-β2 and chemokine ligand 2 levels. High HOXA9 expression in clinical specimens of ovarian cancer was strongly associated with increased abundance of TAMs and intratumoral T-regulatory cells and decreased abundance of CD8(+) tumor-infiltrating lymphocytes. Levels of immunosuppressive cytokines were also elevated in ascites fluid of patients with tumors that highly expressed HOXA9. HOXA9 may, therefore, stimulate ovarian cancer progression by promoting an immunosuppressive microenvironment via paracrine effects on peritoneal macrophages.
    Tipo de documento:
    Referencia
    Referencia del producto:
    17-371
    Nombre del producto:
    EZ-ChIP™

  • Centrosomal targeting of tyrosine kinase activity does not enhance oncogenicity in chronic myeloproliferative disorders. 22015771

    Constitutive tyrosine kinase activation by reciprocal chromosomal translocation is a common pathogenetic mechanism in chronic myeloproliferative disorders. Since centrosomal proteins have been recurrently identified as translocation partners of tyrosine kinases FGFR1, JAK2, PDGFRα and PDGFRβ in these diseases, a role for the centrosome in oncogenic transformation has been hypothesized. In this study, we addressed the functional role of centrosomally targeted tyrosine kinase activity. First, centrosomal localization was not routinely found for all chimeric fusion proteins tested. Second, targeting of tyrosine kinases to the centrosome by creating artificial chimeric fusion kinases with the centrosomal targeting domain of AKAP450 failed to enhance the oncogenic transforming potential in both Ba/F3 and U2OS cells, although phospho-tyrosine-mediated signal transduction pathways were initiated at the centrosome. We conclude that the centrosomal localization of constitutively activated tyrosine kinases does not contribute to disease pathogenesis in chronic myeloproliferative disorders.
    Tipo de documento:
    Referencia
    Referencia del producto:
    05-321X
    Nombre del producto:
    Anti-Phosphotyrosine Antibody, clone 4G10®

  • Impact of Vesicular Stomatitis Virus M Proteins on Different Cellular Functions. 26091335

    Three different matrix (M) proteins termed M1, M2 and M3 have been described in cells infected with vesicular stomatitis virus (VSV). Individual expression of VSV M proteins induces an evident cytopathic effect including cell rounding and detachment, in addition to a partial inhibition of cellular protein synthesis, likely mediated by an indirect mechanism. Analogous to viroporins, M1 promotes the budding of new virus particles; however, this process does not produce an increase in plasma membrane permeability. In contrast to M1, M2 and M3 neither interact with the cellular membrane nor promote the budding of double membrane vesicles at the cell surface. Nonetheless, all three species of M protein interfere with the transport of cellular mRNAs from the nucleus to the cytoplasm and also modulate the redistribution of the splicing factor. The present findings indicate that all three VSV M proteins share some activities that interfere with host cell functions.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • High-performance liquid chromatographic analysis of tamoxifen, toremifene and their major human metabolites. 8376482

    The chromatographic behaviour of tamoxifen, toremifene and their major metabolites was investigated by reversed-phase high-performance liquid chromatography on four stationary phases. Two packings were the usual octadecylsilane type and the other two were octylsilane and octadecylsilane of the type specific for basic compounds. The results provide new insight into variations in selectivity with column type for drugs whose basic properties, owing to the presence of an ionizable nitrogen atom, make their chromatography difficult. The results allow an improvement of the separation of metabolites of tamoxifen and toremifene, two triphenylethylene drugs widely used for the treatment of breast cancer. A method is described for the identification and determination of metabolites formed by incubating the parent drugs with human liver microsomal preparations. The assay has been optimized for the identification and quantification of three major metabolites formed by N-oxidative demethylation of the side-chain, 4-hydroxylation of the aromatic ring and a side-chain deamination followed by hydroxylation. These catalytic activities involve cytochrome P450 enzymes.
    Tipo de documento:
    Referencia
    Referencia del producto:
    12-360
    Nombre del producto:
    Acetyl-Histone H3 (Lys9/14) Peptide

  • Nuclear localization of Src-family tyrosine kinases is required for growth factor-induced euchromatinization. 19245808

    Src-family kinases (SFKs), which participate in various signaling events, are found at not only the plasma membrane but also several subcellular compartments, including the nucleus. Nuclear structural changes are frequently observed during transcription, cell differentiation, senescence, tumorigenesis, and cell cycle. However, little is known about signal transduction in the alteration of chromatin texture. Here, we develop a pixel imaging method for quantitatively evaluating chromatin structural changes. Growth factor stimulation increases euchromatic hypocondensation and concomitant heterochromatic hypercondensation in G(1) phase, and the levels reach a plateau by 30 min, sustain for at least 5 h and return to the basal levels after 24 h. Serum-activated SFKs in the nucleus were more frequently detected in the euchromatin areas than the heterochromatin areas. Nuclear expression of kinase-active SFKs, but not unrelated Syk kinase, drastically increases both euchromatinization and heterochromatinization in a manner dependent on the levels of nuclear tyrosine phosphorylation. However, growth factor stimulation does not induce chromatin structural changes in SYF cells lacking SFKs, and reintroduction of one SFK member into SYF cells can, albeit insufficiently, induce chromatin structural changes. These results suggest that nuclear tyrosine phosphorylation by SFKs plays an important role in chromatin structural changes upon growth factor stimulation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB3446
    Nombre del producto:
    Anti-Heterochromatin Protein-1 α Antibody, clone 2HP-2G9

  • Epigenetic mechanisms for silencing glutathione S-transferase m2 expression by hypermethylated specificity protein 1 binding in lung cancer. 21246532

    BACKGROUND: Glutathione S-transferases M2 (GST-M2) is a detoxifying enzyme. Low expression levels of GST-M2 have been detected in lung cancer cells. However, little is known about the regulation of GST-M2 in lung cancer cells. In this study, the authors investigated the epigenetic regulatory mechanisms of GST-M2 in lung cancer cells.METHODS: The authors evaluated the promoter methylation of GST-M2 in lung cancer cells after treatment with the DNA methyltransferase (DNMT) inhibitor 5\'-aza-2\'-deoxycytidine (5\'-aza-dC). Reporter activity assays, chromatin immunoprecipitation (ChIP), electrophoretic mobility-shift assays, and small interfering RNA (siRNA) assays were used to determine whether the methylation of specificity protein 1 (Sp1) affected binding to the GST-M2 promoter or regulated GST-M2 transcription. Real-time polymerase chain reaction was used to determine GST-M2 and DNMT-3b messenger RNA levels in 73 nonsmall cell lung cancer (NSCLC) tissues.RESULTS: GST-M2 expression was restored after treatment with 5\'-aza-dC in lung cancer cells. GST-M2 exhibited high frequency of promoter hypermethylation in lung cancer cells and NSCLC tumor tissues. CpG hypermethylation abated Sp1 binding to the GST-M2 promoter in lung cancer. Knockdown of Sp1 in normal lung cells reduced GST-M2 expression, and silencing of DNMT-3b increased GST-M2 expression in lung cancer cells. In addition, DNMT-3b expression was significantly higher in lung tumors with low levels of GST-M2 expression than in lung tumors with high levels of GST-M2 expression, especially among women and among patients who had stage I disease.CONCLUSIONS: Epigenetic silencing of GST-M2 was distinguished from Sp1-mediated GST-M2 transcriptional expression. The authors concluded that this represents a mechanism that leads to decreased expression of GST-M2 in lung cancer cells. Cancer 2011. © 2011 American Cancer Society.Copyright © 2011 American Cancer Society.
    Tipo de documento:
    Referencia
    Referencia del producto:
    07-645
    Nombre del producto:
    Anti-Sp1 Antibody

  • The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. 18337823

    Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo
    Nombre del producto:
    Múltiplo

  • Tyrosine phosphorylation of QKI mediates developmental signals to regulate mRNA metabolism. 12682013

    The selective RNA-binding protein QKI is essential for myelination in the central nervous system (CNS). QKI belongs to the family of signal transduction activators of RNA (STARs), characteristic of binding RNA and signaling molecules, therefore is postulated to regulate RNA homeostasis in response to developmental signals. Here we report that QKI acts downstream of the Src family protein tyrosine kinases (Src-PTKs) during CNS myelination. QKI selectively interacted with the mRNA encoding the myelin basic protein (MBP). Such interaction stabilized MBP mRNA and was required for the rapid accumulation of MBP mRNA during active myelinogenesis. We found that the interaction between QKI and MBP mRNA was negatively regulated by Src-PTK-dependent phosphorylation of QKI. During early myelin development, tyrosine phosphorylation of QKI in the developing myelin drastically declined, presumably leading to enhanced interactions between QKI and MBP mRNA, which was associated with the rapid accumulation of MBP mRNA and accelerated myelin production. Therefore, developmental regulation of Src-PTK-dependent tyrosine phosphorylation of QKI suggests a novel mechanism for accelerating CNS myelinogenesis via regulating mRNA metabolism.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB386
    Nombre del producto:
    Anti-Myelin Basic Protein Antibody, a.a. 82-87

  • Muscarinic receptor-mediated bronchoconstriction is coupled to caveolae in murine airways. 20023174

    Cholinergic bronchoconstriction is mediated by M2 and M3 muscarinic receptors (MR). In heart and urinary bladder, MR are linked to caveolin-1 or -3, the structural proteins of caveolae. Caveolae are cholesterol rich, omega-shaped invaginations of the plasma membrane. They provide a scaffold for multiple G-protein receptors and membrane-bound enzymes, thereby orchestrating signaling into the cell's interior. Hence, we hypothesized that airway MR signaling pathways are coupled to caveolae as well. To address this issue we determined the distribution of caveolin-isoforms and M2R in murine and human airways and investigated protein-protein associations by FRET-CLSM-analysis in immunolabeled murine tissue sections. Bronchoconstrictor responses of murine bronchi were recorded in lung slice preparations before and after caveolae disruption by methyl-beta-cyclodextrin, efficiency of this treatment being validated by electron microscopy. KCl-induced bronchoconstriction was unaffected after treatment, demonstrating functional integrity of the smooth muscle. Caveolae disruption decreased muscarine-induced bronchoconstriction in wild-type and abolished it in M2R(-/-) and M3R(-/-) mice. Thus, M2R and M3R signaling pathways require intact caveolae. Furthermore, we identified a presumed skeletal and cardiac myocyte-specific caveolin-isoform, caveolin-3, in human and murine bronchial smooth muscle and found it to be associated with M2R in situ. In contrast, M2R was not associated with caveolin-1, despite an in situ-association of caveolin-1 and caveolin-3 was detected. Here, we demonstrated that M2R- and M3R-mediated bronchoconstriction is caveolae-dependent. Since caveolin-3 is directly associated with M2R, we suggest caveolin-3 as novel regulator of M2R-mediated signaling. Key words: airways, bronchus, caveolin, FRET.,
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB367
    Nombre del producto:
    Anti-Muscarinic Acetylcholine Receptor m2 Antibody, clone M2-2-B3