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51.
Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase 总被引:6,自引:0,他引:6
Levy-Adam F Abboud-Jarrous G Guerrini M Beccati D Vlodavsky I Ilan N 《The Journal of biological chemistry》2005,280(21):20457-20466
The endo-beta-glucuronidase, heparanase, is an enzyme that cleaves heparan sulfate at specific intra-chain sites, yielding heparan sulfate fragments with appreciable size and biological activities. Heparanase activity has been traditionally correlated with cell invasion associated with cancer metastasis, angiogenesis, and inflammation. In addition, heparanase up-regulation has been documented in a variety of primary human tumors, correlating with increased vascular density and poor postoperative survival, suggesting that heparanase may be considered as a target for anticancer drugs. In an attempt to identify the protein motif that would serve as a target for the development of heparanase inhibitors, we looked for protein domains that mediate the interaction of heparanase with its heparan sulfate substrate. We have identified three potential heparin binding domains and provided evidence that one of these is mapped at the N terminus of the 50-kDa active heparanase subunit. A peptide corresponding to this region (Lys(158)-Asp(171)) physically associates with heparin and heparan sulfate. Moreover, the peptide inhibited heparanase enzymatic activity in a dose-responsive manner, presumably through competition with the heparan sulfate substrate. Furthermore, antibodies directed to this region inhibited heparanase activity, and a deletion construct lacking this domain exhibited no enzymatic activity. NMR titration experiments confirmed residues Lys(158)-Asn(162) as amino acids that firmly bound heparin. Deletion of a second heparin binding domain sequence (Gln(270)-Lys(280)) yielded an inactive enzyme that failed to interact with cell surface heparan sulfate and hence accumulated in the culture medium of transfected HEK 293 cells to exceptionally high levels. The two heparin/heparan sulfate recognition domains are potentially attractive targets for the development of heparanase inhibitors. 相似文献
52.
53.
Tomáš Vaněk Daniela Veselá Jana Malá Radka Podlipná David Šaman Jitka Kohoutová 《Biotechnology letters》1996,18(5):501-504
In callus cultures of Taxus baccata grown on agar media according to Murashige and Skoog supplemented with different growth hormones 8 taxol analogues were identified. 相似文献
54.
Impaired carotenogenesis can affect organization and functionality of etioplast membranes 总被引:1,自引:0,他引:1
Isabella Moro Francesca Dalla Vecchia Nicoletta La Rocca Flavia Navari-Izzo Mike Frank Quartacci Daniela Di Baccio Wolfhart Rüdiger Nicoletta Rascio 《Physiologia plantarum》2004,122(1):123-132
The effects of impaired carotenogenesis on plastid membrane organization, functionality and stability were studied in etiolated barley plants grown at 20 and 30°C. The plants were treated with norflurazon or amitrole, two herbicides affecting phytoene desaturation and lycopene cyclization, respectively. At 20°C, the amitrole-treated etioplasts, which accumulated lycopene in their inner membranes, exhibited disorganized prolamellar bodies, containing a prevalent form of non-phototransformable protochlorophyllide (Pchlide). They also showed a certain difficulty in reducing the phototransformable pigment to chlorophyllide when exposed to light, and were unable to reform the active ternary complex [protochlorophyllide–oxidoreductase (POR)–Pchlide–NADPH] when placed back in darkness. No ultrastructural alterations were found in norflurazon-treated etioplasts, with carotenogenesis inhibited at the phytoene desaturation step. In these latter organelles, Pchlide, whose forms were comparable with those of the control etioplasts, was photoreduced quickly after illumination and the ternary complex was reformed during a subsequent dark period. Thus, the impaired carotenogenesis leading to the accumulation of lycopene showed greater interference with the etioplast membrane arrangement and functionality than did the earlier interruption of the biosynthetic pathway at the phytoene level. This might be due to the different interactions of the distinct carotenoid precursors with other membrane components. However, in etioplasts of norflurazon-treated plants, a rise in growth temperature caused a partial demolition of prolamellar bodies, showing a lowered thermostability of the carotenoid-deficient membranes. This latter effect strengthens the concept that a correct and complete carotenogenesis pathway, leading to the synthesis of polar carotenoids (i.e. xanthophylls), is required for the maintenance of stable plastid membranes. 相似文献
55.
Timóteo CG Guilherme M Penas D Folgosa F Tavares P Pereira AS 《The Biochemical journal》2012,445(1):125-133
β?-GPI (β?-glycoprotein I) is a plasma glycoprotein ascribed with an anti-angiogenic function; however, the biological role and molecular basis of its action in cell migration remain unknown. The aim of the present study was to assess the contribution of β?-GPI to HAEC (human aortic endothelial cell) migration and the details of its underlying mechanism. Using wound healing and Boyden chamber assays, we found that β?-GPI inhibited endothelial cell migration, which was restored by its neutralizing antibody. NF-κB (nuclear factor κB) inhibitors and lentiviral siRNA (small interfering RNA) silencing of NF-κB significantly attenuated the inhibitory effect of β?-GPI on cell migration. Moreover, β?-GPI was found to induce IκBα (inhibitor of NF-κB) phosphorylation and translocation of p65 and p50. We further demonstrated that mRNA and protein levels of eNOS [endothelial NO (nitric oxide) synthase] and NO production were all increased by β?-GPI and these effects were remarkably inhibited by NF-κB inhibitors and siRNAs of p65 and p50. Furthermore, β?-GPI-mediated inhibition of cell migration was reversed by eNOS inhibitors and eNOS siRNAs. The findings of the present study provide novel insight into the ability of β?-GPI to inhibit endothelial cell migration predominantly through the NF-κB/eNOS/NO signalling pathway, which indicates a potential direction for clinical therapy in vascular diseases. 相似文献
56.
Yefi R Ponce DP Niechi I Silva E Cabello P Rodriguez DA Marcelain K Armisen R Quest AF Tapia JC 《Journal of cellular biochemistry》2011,112(11):3167-3175
Augmented expression of protein kinase CK2 is associated with hyperproliferation and resistance to apoptosis in cancer cells. Effects of CK2 are at least partially linked to signaling via the Wnt/β-catenin pathway, which is dramatically enhanced in colon cancer. Cyclooxygenase-2 (COX-2), a Wnt/β-catenin target gene, has been associated with enhanced cancer progression and metastasis. However, the possibility that a connection may exist between CK2 and COX-2 has not been explored previously. Here we investigated changes in COX-2 expression and activity upon CK2 modulation and evaluated how these changes affected cell viability. COX-2 expression and cell viability decreased upon selective inhibition of COX-2 with SC-791 or CK2 with 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), both in human colon (HT29-ATCC, HT29-US, DLD-1) and breast (ZR-75) cancer cells, as well as in human embryonic kidney (HEK-293T) cells. On the other hand, ectopic CK2α expression promoted up-regulation of COX-2 by activating the Wnt/β-catenin pathway in HEK-293T cells. Noteworthy, over-expression of either CK2α, β-catenin or COX-2, as well as supplementation of the medium with prostaglandin E2 (PGE2), all were individually sufficient to overcome limitations in cell viability triggered by CK2 inhibition either upon addition of DMAT or over-expression of a dominant negative CK2α variant. Altogether, these findings provide new insight to the role of CK2 in cancer by up-regulating COX-2 expression and thereby PGE2 production. 相似文献
57.
Focused glycomic analysis of the N-linked glycan biosynthetic pathway in ovarian cancer 总被引:1,自引:0,他引:1
Abbott KL Nairn AV Hall EM Horton MB McDonald JF Moremen KW Dinulescu DM Pierce M 《Proteomics》2008,8(16):3210-3220
58.
Maura Marinozzi Andrea Carotti Roccaldo Sardella Federica Buonerba Federica Ianni Benedetto Natalini Daniela Passeri Giovanni Rizzo Roberto Pellicciari 《Bioorganic & medicinal chemistry》2013,21(13):3780-3789
An asymmetric synthetic strategy was designed for the preparation of the four possible diastereoisomers of 3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one, a non-steroidal FXR agonist, we recently discovered following a virtual screening approach. The results obtained from an AlphaScreen assay clearly demonstrated that only the isomer endowed with 4R,6S absolute configuration is responsible for the biological activity. A deep investigation of the different putative binding modes adopted by these enantiomerically pure ligands using computational modeling studies confirmed the enantioselectivity of FXR towards this class of molecules. 相似文献
59.
Carina Proença Marisa Freitas Daniela Ribeiro Eduardo F. T. Oliveira Joana L. C. Sousa Sara M. Tomé 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):1216-1228
α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme’s activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure–activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG. 相似文献
60.
Siegmund D Hadwiger P Pfizenmaier K Vornlocher HP Wajant H 《Molecular medicine (Cambridge, Mass.)》2002,8(11):725-732
BACKGROUND: Most tumors express death receptors and their activation represents a potential selective approach in cancer treatment. The most promising candidate for tumor selective death receptor-activation is tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L, which activates the death receptors TRAIL-R1 and TRAIL-R2, and induces apoptosis preferentially in tumor cells but not in normal tissues. However, many cancer cells are not or only moderately sensitive towards TRAIL and require cotreatment with irradiation or chemotherapy to yield a therapeutically reasonable apoptotic response. Because chemotherapy can have a broad range of unwanted side effects, more specific means for sensitizing tumor cells for TRAIL are desirable. The expression of the cellular FLICE-like inhibitory protein (cFLIP) is regarded as a major cause of TRAIL resistance. We therefore analyzed the usefulness of targeting FLIP to sensitize tumor cells for TRAIL-induced apoptosis. MATERIALS AND METHODS: To selectively interfere with expression of cFLIP short double-stranded RNA oligonucleotides (small interfering RNAs [siRNAs]) were introduced in the human cell lines SV80 and KB by electroporation. Effects of siRNA on FLIP expression were analyzed by Western blotting and RNase protection assay and correlated with TRAIL sensitivity upon stimulation with recombinant soluble TRAIL and TRAIL-R1- and TRAIL-R2-specific agonistic antibodies. RESULTS: FLIP expression can be inhibited by RNA interference using siRNAs, evident from reduced levels of FLIP-mRNA and FLIP protein. Inhibition of cFLIP expression sensitizes cells for apoptosis induction by TRAIL and other death ligands. In accordance with the presumed function of FLIP as an inhibitor of death receptor-induced caspase-8 activation, down-regulation of FLIP by siRNAs enhanced TRAIL-induced caspase-8 activation. CONCLUSION: Inhibition of FLIP expression was sufficient to sensitize tumor cells for TRAIL-induced apoptosis. The combination of TRAIL and FLIP-targeting siRNA could therefore be a useful strategy to attack cancer cells, which are resistant to TRAIL alone. 相似文献