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  • Inhibition of cytokinesis and akt phosphorylation by chaetoglobosin K in ras-transformed epithelial cells. 16254733

    PURPOSE: Chaetoglobosin K (ChK), a bioactive natural product previously shown to have anti-tumor promoting activity in glial cells and growth inhibitory effects in ras-transformed fibroblasts, inhibited anchorage-dependent and anchorage-independent growth in ras-transformed liver epithelial cells. The purpose of this study was to identify cellular targets of ChK that mediate its anti-tumor effects. METHODS: Anchorage-independent cell growth assays, using soft agar-coated dishes, and anchorage-dependent growth assays were performed on transformed WB- ras1 cells. Phase/contrast and fluorescent microscopy were used to visualize cell morphological changes and DAPI-stained nuclei. Analyses of p21 Ras membrane versus cytosolic forms, p44/42 mitogen-activated protein kinase (MAPK) phosphorylation, Akt kinase phosphorylation and connexin 43 phosphorylation were performed by Western blotting. Gap junction-mediated cellular communication was measured by fluorescent dye transfer. RESULTS: Treatment of WB- ras1 cells with a non-cytotoxic dose of ChK inhibited both anchorage-dependent and anchorage-independent growth. Inhibited cells were generally larger and less spindle-shaped in morphology than vehicle-treated cells, many of which were multinucleate. Removal of ChK induced cytokinesis and a return to predominantly single-nucleate cells, suggesting that ChK inhibits cytokinesis. The proportion of membrane-associated versus cytosolic forms of p21 Ras was unchanged by ChK treatment, suggesting that ChK does not act as a farnesylation inhibitor. ChK treatment decreased the level of phosphorylation of Akt kinase, a key signal transducer of the Phosphatidylinositol 3-kinase pathway. In contrast, ChK had no effect on phosphorylation of p44/42 MAPK, which mediates the MAPK/ERK Ras effector pathway. Phosphorylation of the gap junction protein, connexin 43, shown previously to increase following treatment with other anti-Ras compounds, was also not altered by ChK, which correlated with its lack of effect on gap junction-mediated cellular communication. CONCLUSIONS: Our results demonstrate that ChK inhibits Akt kinase phosphorylation and cytokinesis in ras-transformed cells, which likely contribute to its ability to inhibit tumorigenic growth.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB3086
    Nombre del producto:
    Anti-Ryanodine Receptor Antibody, clone RYR.1

  • Csk homologous kinase associates with RAFTK/Pyk2 in breast cancer cells and negatively regulates its activation and breast cancer cell migration. 12063569

    Our recent observations indicated that RAFTK (also termed Pyk2 and CAK-beta) participated in intracellular signaling upon heregulin (HRG) stimulation and promoted breast carcinoma invasion. Furthermore, studies from our group indicate that the Csk homologous kinase (CHK), a member of the Csk family, directly associates with HER2/Neu and down-regulates HER2/Neu-mediated Src kinase activation in breast cancer cells upon heregulin stimulation. Since activation of RAFTK is associated with the activity of Src family kinases, we analyzed whether CHK is capable of opposing HRG-induced activation of RAFTK. Stimulation of human T47D breast cancer cells with HRG induced the tyrosine phosphorylation of RAFTK and its association with CHK in vitro and in vivo. This interaction was mediated through the Src binding site (amino acid residue at 402) of RAFTK and the SH2 domain of CHK. RAFTK phosphorylation downstream of the activated HER2/Neu was greatly reduced in the presence of CHK. Maximal inhibition of RAFTK phosphorylation by CHK required the kinase activity of CHK. Furthermore, CHK inhibited the tyrosine phosphorylation of the focal adhesion-associated protein, paxillin, and inhibited HRG-induced T47D breast cancer cell migration. These findings indicate the role of CHK as a negative regulator in HRG- and RAFTK-mediated intracellular signaling in breast cancer cells.
    Tipo de documento:
    Referencia
    Referencia del producto:
    Múltiplo

  • PLK-1 asymmetry contributes to asynchronous cell division of C. elegans embryos. 18305005

    Acquisition of lineage-specific cell cycle duration is an important feature of metazoan development. In Caenorhabditis elegans, differences in cell cycle duration are already apparent in two-cell stage embryos, when the larger anterior blastomere AB divides before the smaller posterior blastomere P1. This time difference is under the control of anterior-posterior (A-P) polarity cues set by the PAR proteins. The mechanisms by which these cues regulate the cell cycle machinery differentially in AB and P1 are incompletely understood. Previous work established that retardation of P1 cell division is due in part to preferential activation of an ATL-1/CHK-1 dependent checkpoint in P1, but how the remaining time difference is controlled is not known. Here, we establish that differential timing relies also on a mechanism that promotes mitosis onset preferentially in AB. The polo-like kinase PLK-1, a positive regulator of mitotic entry, is distributed in an asymmetric manner in two-cell stage embryos, with more protein present in AB than in P1. We find that PLK-1 asymmetry is regulated by A-P polarity cues through preferential protein retention in the embryo anterior. Importantly, mild inactivation of plk-1 by RNAi delays entry into mitosis in P1, but not in AB, in a manner that is independent of ATL-1/CHK-1. Together, our findings support a model in which differential timing of mitotic entry in C. elegans embryos relies on two complementary mechanisms: ATL-1/CHK-1-dependent preferential retardation in P1 and PLK-1-dependent preferential promotion in AB, which together couple polarity cues and cell cycle progression during early development.
    Tipo de documento:
    Referencia
    Referencia del producto:
    MAB3580
    Nombre del producto:
    Anti-Green Fluorescent Protein Antibody