Previous studies showed that sub-micromolar concentrations of the microtubule-targeting herbicide propyzamide cause a right-handed helical arrangement of cortical microtubule arrays and left-handed twisting in elongating Arabidopsis epidermal cells. When seedlings were grown in the presence of 1-2 microM propyzamide or 50-100 nM oryzalin, we show that microtubules spent more time in a paused state in which they exhibited little net change in length. The drug treatment also resulted in slower growth and shortening velocities, increased catastrophe, and an overall decrease in microtubule turnover. A reduction in microtubule dynamic turnover may underlie the drug-induced rearrangement of cortical arrays.
Helicobacter pylori infection induces chronic inflammation that contributes to gastric tumorigenesis. Tumor necrosis factor (TNF-a) is a proinflammatory cytokine, and polymorphism in the TNF-a gene increases the risk of gastric cancer. We herein investigated the role of TNF-a in gastric tumorigenesis using Gan mouse model, which recapitulates human gastric cancer development. We crossed Gan mice with TNF-a (Tnf) or TNF-a receptor TNFR1 (Tnfrsf1a) knockout mice to generate Tnf À / À Gan and Tnfrsf1a À / À Gan mice, respectively, and examined their tumor phenotypes. Notably, both Tnf À / À Gan mice and Tnfrsf1a À / À Gan mice showed similar, significant suppression of gastric tumor growth compared with control Tnf þ / þ or Tnfrsf1a þ / þ Gan mice. These results indicate that TNF-a signaling through TNFR1 is important for gastric tumor development. Bone marrow (BM) transplantation experiments showed that TNF-a expressed by BM-derived cells (BMDCs) stimulates the TNFR1 on BMDCs by an autocrine or paracrine manner, which is important for gastric tumor promotion. Moreover, the microarray analysis and colony formation assay indicated that NADPH oxidase organizer 1 (Noxo1) and Gna14 are induced in tumor epithelial cells in a TNF-a-dependent manner, and have an important role in tumorigenicity and tumor-initiating cell property of gastric cancer cells. Accordingly, it is possible that the activation of TNF-a/TNFR1 signaling in the tumor microenvironment promotes gastric tumor development through induction of Noxo1 and Gna14, which contribute to maintaining the tumor cells in an undifferentiated state. The present results indicate that targeting the TNF-a/TNFR1 pathway may be an effective preventive or therapeutic strategy for gastric cancer.
Genetic alterations in the TGFb signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of
Reversible protein phosphorylation regulates many cellular processes, including the dynamics and organization of the microtubule cytoskeleton, but the events mediating it are poorly understood. A semidominant phs1-1 allele of the Arabidopsis thaliana PROPYZAMIDE-HYPERSENSITIVE 1 locus exhibits phenotypes indicative of compromised cortical microtubule functions, such as left-handed helical growth of seedling roots, defective anisotropic growth at low doses of microtubule-destabilizing drugs, enhancement of the temperature-sensitive microtubule organization1-1 phenotype, and less ordered and more fragmented cortical microtubule arrays compared with the wild type. PHS1 encodes a novel protein similar to mitogen-activated protein kinase (MAPK) phosphatases. In phs1-1, a conserved Arg residue in the noncatalytic N-terminal region is exchanged with Cys, and the mutant PHS1 retained considerable phosphatase activity in vitro. In mammalian MAPK phosphatases, the corresponding region serves as a docking motif for MAPKs, and analogous Arg substitutions severely inhibit the kinase-phosphatase association. Transgenic studies indicate that the phs1-1 mutation acts dominant negatively, whereas the null phs1-2 allele is recessive embryonic lethal. We propose that the PHS1 phosphatase regulates more than one MAPK and that a subset of its target kinases is involved in the organization of cortical microtubules.
Cells at the elongation zone expand longitudinally to form the straight central axis of plant stems, hypocotyls and roots, and transverse cortical microtubule arrays are generally recognized to be important for the anisotropic growth. Recessive mutations in either of two Arabidopsis thaliana SPIRAL loci, SPR1 or SPR2, reduce anisotropic growth of endodermal and cortical cells in roots and etiolated hypocotyls, and induce right-handed helical growth in epidermal cell files of these organs. spr2 mutants additionally show right-handed twisting in petioles and petals. The spr1spr2 double mutant's phenotype is synergistic, suggesting that SPR1 and SPR2 act on a similar process but in separate pathways in controlling cell elongation. Interestingly, addition of a low dose of either of the microtubule-interacting drugs propyzamide or taxol in the agar medium was found to reduce anisotropic expansion of endodermal and cortical cells at the root elongation zone of wild-type seedlings, resulting in left-handed helical growth. In both spiral mutants, exogenous application of these drugs reverted the direction of the epidermal helix, in a dose-dependent manner, from right-handed to left-handed; propyzamide at 1 microM and taxol at 0.2-0.3 microM effectively suppressed the cell elongation defects of spiral seedlings. The spr1 phenotype is more pronounced at low temperatures and is nearly suppressed at high temperatures. Cortical microtubules in elongating epidermal cells of spr1 roots were arranged in left-handed helical arrays, whereas the highly isotropic cortical cells of etiolated spr1 hypocotyls showed microtubule arrays with irregular orientations. We propose that a microtubule-dependent process and SPR1/SPR2 act antagonistically to control directional cell elongation by preventing elongating cells from potential twisting. Our model may have implicit bearing on the circumnutation mechanism.
Background: The National Bio Resource Project for the Rat in Japan (NBRP-Rat) is focusing on collecting, preserving and distributing various rat strains, including spontaneous mutant, transgenic, congenic, and recombinant inbred (RI) strains. To evaluate their value as models of human diseases, we are characterizing them using 109 phenotypic parameters, such as clinical measurements, internal anatomy, metabolic parameters, and behavioral tests, as part of the Rat Phenome Project. Here, we report on a set of 357 simple sequence length polymorphism (SSLP) markers and 122 rat strains, which were genotyped by the marker set.
Abstract. More than 300 bio-active compounds have been identified from bee propolis in various regions of the world. The objective of this study was to examine whether the ethanol extracts of Chinese and Brazilian propolis may exert anticancer activities in four human colon carcinoma cell lines, namely CaCo2, HCT116, HT29 and SW480. Propolis samples were extracted with ethanol, and the crude extracts were dissolved in dimethylsulfoxide and used for the experiments. In HCT116, HT29 and SW480 cell lines, the extracts of both Chinese and Brazilian propolis caused a marked dose-dependent growth inhibition, with IC 50 values in the range of 4-41 μg/ml. In HCT116 cell line, Chinese propolis extract induced apoptosis in the cells after 72 h of treatment. In addition, Chinese propolis extract caused a dose-dependent increase in the cellular mRNA levels of p21 CIP1 and p53 in the HCT116 cell line. These findings indicate that the ethanol extracts of propolis contain components that may have anticancer activity. Thus, propolis and related products may provide a novel approach to the chemoprevention and treatment of human colon carcinoma. IntroductionThere is growing interest in the use of natural products to aid in the maintenance of human health. Natural products contain a wide variety of chemical compounds that have potent biological effects, including anticancer activity (1). Identification of the active components and their mechanism of action is important to assess their potential for clinical use and possible diverse side effects. Propolis is a natural product derived from various plant resins collected by honeybees, and has been used as a folk medicine for centuries in Europe, North and South America, China and Japan (2). Propolis has been reported to exhibit a broad spectrum of activities including antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, hepatoprotective, and anticancer properties (2,3). Propolis from Europe, North and South America, Asia and Africa differ in their composition because of the differences in the local vegetation (2,3). The medical application of propolis has led to increased interest in its chemical compositions and its botanical origins since polyphenol compounds and their derivatives have been identified in propolis (2,3).Colon carcinoma is a common malignancy ranking third in frequency on a world wide basis and causes about 500,000 deaths annually (4). This malignancy is most common in developed countries of Western world, and mortality rate of this disease is rising (4). It is thought that one-third of human carcinoma might be associated with dietary habits and lifestyle (5) and dietary factors are known to be critical modulators of the development of human colon carcinoma (6,7). Despite recent clinical advances, colon carcinoma still remains a major issue because of its incidence, morbidity, and mortality (4,8,9). One promising approach to reduce the incidence and improve the prognosis of this malignancy may be chemoprevention (1,10).Although the above-described fi...
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