12 research outputs found

    Abnormal hedgehog pathway in myelodysplastic syndrome and its impact on patients' outcome

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    sem informação10012e491e493CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçãosem informaçã

    Imatinib restores vasp activity and its interaction with zyxin in bcr-abl leukemic cells

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    Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-ABL oncoprotein. The presence of BCR-ABL protein drives oncogenesis in patients with chronic myeloid leukemia (CML) due to a constitutive activation of tyrosine kinase activity. However, the function of VASP and Zyxin in BCR-ABL pathway and the role of VASP in CML cells remain unknown. In vitro experiments using K562 cells showed the involvement of VASP in BCR-ABL signaling. VASP and Zyxin inhibition decreased the expression of anti-apoptotic proteins, BCL2 and BCL-XL. Imatinib induced an increase in phosphorylation at Ser157 of VASP and decreased VASP and BCR-ABL interaction. VASP did not interact with Zyxin in K562 cells; however, after Imatinib treatment, this interaction was restored. Corroborating our data, we demonstrated the absence of phosphorylation at Ser157 in VASP in the bone marrow of CML patients, in contrast to healthy donors. Phosphorylation of VASP on Ser157 was restored in Imatinib responsive patients though not in the resistant patients. Therefore, we herein identified a possible role of VASP in CML pathogenesis, through the regulation of BCR-ABL effector proteins or the absence of phosphorylation at Ser157 in VASP.Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-AB18532388395CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçãosem informaçã

    Imatinib Restores Vasp Activity And Its Interaction With Zyxin In Bcr-abl Leukemic Cells

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    Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-ABL oncoprotein. The presence of BCR-ABL protein drives oncogenesis in patients with chronic myeloid leukemia (CML) due to a constitutive activation of tyrosine kinase activity. However, the function of VASP and Zyxin in BCR-ABL pathway and the role of VASP in CML cells remain unknown. In vitro experiments using K562 cells showed the involvement of VASP in BCR-ABL signaling. VASP and Zyxin inhibition decreased the expression of anti-apoptotic proteins, BCL2 and BCL-XL. Imatinib induced an increase in phosphorylation at Ser157 of VASP and decreased VASP and BCR-ABL interaction. VASP did not interact with Zyxin in K562 cells; however, after Imatinib treatment, this interaction was restored. Corroborating our data, we demonstrated the absence of phosphorylation at Ser157 in VASP in the bone marrow of CML patients, in contrast to healthy donors. Phosphorylation of VASP on Ser157 was restored in Imatinib responsive patients though not in the resistant patients. Therefore, we herein identified a possible role of VASP in CML pathogenesis, through the regulation of BCR-ABL effector proteins or the absence of phosphorylation at Ser157 in VASP.18532388395Goss, V.L., Lee, K.A., Moritz, A., Nardone, J., Spek, E.J., MacNeill, J., Rush, J., Polakiewicz, R.D., A common phosphotyrosine signature for the Bcr-Abl kinase (2006) Blood, 107, pp. 4888-4897Druker, B.J., Talpaz, M., Resta, D.J., Peng, B., Buchdunger, E., Ford, J.M., Lydon, N.B., Sawyers, C.L., Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia (2001) N. Engl. J. Med., 344, pp. 1031-1037Kuroda, J., Puthalakath, H., Cragg, M.S., Kelly, P.N., Bouillet, P., Huang, D.C., Kimura, S., Strasser, A., Bim and Bad mediate imatinib-induced killing of Bcr/Abl+leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic (2006) Proc. Natl. Acad. Sci. U. S. A., 103, pp. 14907-14912Kuroda, J., Kimura, S., Strasser, A., Andreeff, M., O'Reilly, L.A., Ashihara, E., Kamitsuji, Y., Maekawa, T., Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia (2007) Cell Death Differ., 14, pp. 1667-1677Kuroda, J., Kimura, S., Andreeff, M., Ashihara, E., Kamitsuji, Y., Yokota, A., Kawata, E., Maekawa, T., ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms (2008) Br. J. 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Biol., 17, pp. 1947-1958Sperry, R.B., Bishop, N.H., Bramwell, J.J., Brodeur, M.N., Carter, M.J., Fowler, B.T., Lewis, Z.B., Hansen, M.D., Zyxin controls migration in epithelial-mesenchymal transition by mediating actin-membrane linkages at cell-cell junctions (2010) J. Cell. Physiol., 222, pp. 612-624Grange, J., Moody, J.D., Ascione, M.P., Hansen, M.D., Zyxin-VASP interactions alter actin regulatory activity in zyxin-VASP complexes (2013) Cell. Mol. Biol. Lett., 18, pp. 1-10Drees, B., Friederich, E., Fradelizi, J., Louvard, D., Beckerle, M.C., Golsteyn, R.M., Characterization of the interaction between zyxin and members of the Ena/vasodilator-stimulated phosphoprotein family of proteins (2000) J. Biol. Chem., 275, pp. 22503-22511Hansen, M.D., Beckerle, M.C., Opposing roles of zyxin/LPP ACTA repeats and the LIM domain region in cell-cell adhesion (2006) J. Biol. 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Commun., 404, pp. 780-784Han, G., Fan, B., Zhang, Y., Zhou, X., Wang, Y., Dong, H., Wei, Y., Wei, L., Positive regulation of migration and invasion by vasodilator-stimulated phosphoprotein via Rac1 pathway in human breast cancer cells (2008) Oncol. Rep., 20, pp. 929-939Tao, Y., Chen, Y.C., Wang, Y., Zhang, Z.J., Xu, W.R., Phosphorylated vasodilator-stimulated phosphoprotein is localized on mitotic spindles of the gastric cancer cell line SGC-7901 (2006) World J. Gastroenterol., 12, pp. 7478-7481Sy, S.M., Lai, P.B., Pang, E., Wong, N.L., To, K.F., Johnson, P.J., Wong, N., Novel identification of zyxin upregulations in the motile phenotype of hepatocellular carcinoma (2006) Mod. Pathol., 19, pp. 1108-1116van der Gaag, E.J., Leccia, M.T., Dekker, S.K., Jalbert, N.L., Amodeo, D.M., Byers, H.R., Role of zyxin in differential cell spreading and proliferation of melanoma cells and melanocytes (2002) J. Investig. 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    Computed tomography-based skeletal segmentation for quantitative PET metrics of bone involvement in multiple myeloma

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    FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPPurpose: Quantifications in nuclear medicine are occasionally limited by the lack of standardization for defining volumes of interest (VOIs) on functional images. In the present article, we propose the use of computed tomography (CT)-based skeletal segmen414377382FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2009/54065-02018/00654-4The authors would like to thank the Nuclear and Energy Research Institute (IPEN-CNEN), São Paulo, Brazil, for supplying the radiopharmaceuticals used in the present project (IPEN/UNICAMP agreement No. 01342000458/2017-15). The authors are grateful for th

    Seasonal and spatial patterns in cellular energy allocation in the estuarine mysid Neomysis integer (Crustacea: Mysidacea) of the Scheldt estuary (The Netherlands)

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    Myelodysplastic syndromes (MDS) are clonal disorders involving hematopoietic stem cells (HSC) characterized by ineffective hematopoiesis. In addition to HSC defects, a defective hematopoiesis supporting capacity of mesenchymal stromal cells (MSCs) in the microenvironment niche has been implicated in MDS pathophysiology. The interaction between the dysfunctional MSCs MDS and HSC regulates diverse adhesion-related processes, such as progenitor cell survival, proliferation, differentiation, and self-renewal. As previously reported, a microarray analysis identified serine protease inhibitor kunitz-type 2 (SPINT2), an inhibitor of hepatocyte growth factor (HGF) activation, to be downregulated in MSCs from MDS patients. To define the role of SPINT2 in MDS hematopoietic microenvironment, an analysis of the effect of SPINT2 silencing in MSCs was carried out. We herein reported significantly lower levels of SPINT2 whereas HGF was expressed at higher levels in MSCs from MDS patients compared with healthy controls. SPINT2 underexpression results in an increased expression, production, and secretion of HGF and stromal cell-derived factor 1 (SDF-1) by MSCs. An increased adhesion of normal HSC or malignant cells onto MSCs silenced for SPINT2 was also observed. The altered MSCs adhesion in SPINT2-knockdown cells was correlated with increased CD49b and CD49d expression and with a decrease in CD49e expression. Our results suggest that the SPINT2 underexpression in the MSC from MDS patients is probably involved in the adhesion of progenitors to the bone marrow niche, through an increased HGF and SDF-1 signaling pathway.231109-2
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