排序方式: 共有298条查询结果,搜索用时 15 毫秒
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Lijs Beke Cenk Kig Joannes?T. M. Linders Shannah Boens An Boeckx Erika van Heerde Marc Parade An De Bondt Ilse Van den Wyngaert Tarig Bashir Souichi Ogata Lieven Meerpoel Aleyde Van Eynde Christopher?N. Johnson Monique Beullens Dirk Brehmer Mathieu Bollen 《Bioscience reports》2015,35(6)
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing. In the present study, we have explored the biological function of MELK using MELK-T1, a novel and selective small-molecule inhibitor. Strikingly, MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELK-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (CHK2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold. 相似文献
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Cell-free analysis of tail-anchor protein targeting to membranes 总被引:3,自引:0,他引:3
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Kenneth N. Mertens Sofia Ribeiro Ilham Bouimetarhan Hulya Caner Nathalie Combourieu Nebout Barrie Dale Anne De Vernal Marianne Ellegaard Mariana Filipova Anna Godhe Evelyne Goubert Kari Grøsfjeld Ulrike Holzwarth Ulrich Kotthoff Suzanne A.G. Leroy Laurent Londeix Fabienne Marret Kazumi Matsuoka Peta J. Mudie Lieven Naudts Stephen Louwye 《Marine Micropaleontology》2009,70(1-2):54-69
A biometrical analysis of the dinoflagellate cyst Lingulodinium machaerophorum [Deflandre, G., Cookson, I.C., 1955. Fossil microplankton from Australia late Mesozoic and Tertiary sediments. Australian journal of Marine and Freshwater Research 6: 242–313.] Wall, 1967 in 144 globally distributed surface sediment samples revealed that the average process length is related to summer salinity and temperature at a water depth of 30 m by the equation (salinity/temperature) = (0.078?average process length + 0.534) with R2 = 0.69. This relationship can be used to reconstruct palaeosalinities, albeit with caution. The particular ecological window can be associated with known distributions of the corresponding motile stage Lingulodinium polyedrum (Stein) Dodge, 1989. Confocal laser microscopy showed that the average process length is positively related to the average distance between process bases (R2 = 0.78), and negatively related to the number of processes (R2 = 0.65). These results document the existence of two end members in cyst formation: one with many short, densely distributed processes and one with a few, long, widely spaced processes, which can be respectively related to low and high salinity/temperature ratios. Obstruction during formation of the cysts causes anomalous distributions of the processes. From a biological perspective, processes function to facilitate sinking of the cysts through clustering. 相似文献
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Steinernemar robustispiculum n. sp. (Rhabditida: Steinernematidae) was isolated from woodland in Chumomray National Park, Sason, Sathay, Kontum, Vietnam. Its morphology, morphometrics, cross-hybridisation and the ITS-rDNA sequence analysis revealed that S. robustispiculum clearly differs from other known Steinernema spp. As in the cases of S. intermedium (Poinar, 1985), S. robustispiculum has very robust spicules, but it can be distinguished by the longer tail of the infective juvenile, lower E%, shorter spicules, the shape of the spicules, the number of genital papillae in the caudal region and the presence of a mucron on the male tail. S. robustispiculum has a lateral field resembling that of S. sangi Phan, Nguyen & Moens, 2001, but can be distinguished by a higher E%, higher D%, smaller length to width ratio of the spicules and the morphology of both the spicule head (manubrium) and the dorsal lobe of the spicule. The morphometrics of infective juveniles of S. robustispiculum are similar to those of S. monticolum Stock, Choo & Kaya, 1997; these species can be distingusihed by the position of the excretory pore, the smaller length to width ratio of the spicules, and the length and morphology of the spicule head (manubrium). The phylogenetic relationships within Steinernema Travassos, 1927, including the newly sequenced Vietnamese species S. robustispiculum n. sp., S. loci Phan, Nguyen & Moens, 2001, S. thanhi Phan, Nguyen & Moens, 2001 and S. sangi, are presented based on analyses of the ITS-rDNA. The ITS RFLP profiles obtained from 17 different restriction enzymes are also presented. 相似文献
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Shi J Du J Ma T Pankiewicz KW Patterson SE Tharnish PM McBrayer TR Stuyver LJ Otto MJ Chu CK Schinazi RF Watanabe KA 《Bioorganic & medicinal chemistry》2005,13(5):1641-1652
Based on the discovery of (2'R)-d-2'-deoxy-2'-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of d- and l-2'-deoxy-2'-fluororibonucleosides with modifications at 5- and/or 4-positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The key step in the synthesis, the introduction of 2'-fluoro group, was achieved by either fluorination of 2,2'-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compound, namely (2'R)-d-2'-deoxy-2',5-difluorocytidine (13), demonstrated potent anti-HCV activity and toxicity to ribosomal RNA. The replacement of the 4-amino group with a thiol group resulted in the loss of activity, while the 4-methylthio substituted analogue (25) exhibited inhibition of ribosomal RNA. As N(4)-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, we combined the two functionalities of the N(4)-hydroxyl and the 2'-fluoro into one molecule, resulting (2'R)-d-2'-deoxy-2'-fluoro-N(4)-hydroxycytidine (23). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the l-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot always predict anti-HCV activity. 相似文献
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Hassan AE Wang P McBrayer TR Tharnish PM Stuyver LJ Schinazi RF Otto MJ Watanabe KA 《Nucleosides, nucleotides & nucleic acids》2005,24(5-7):961-964
A series of N3, 5-Anhydro-4-(beta-D-ribofuranosyl)-8-azapurin-2-ones were prepared in multistep reactions from uridine as potential anti-hepatitis C virus (HCV) agents. The synthetic details as well as biological evaluations are discussed. 相似文献
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Dlugosz PJ Billen LP Annis MG Zhu W Zhang Z Lin J Leber B Andrews DW 《The EMBO journal》2006,25(11):2287-2296
Bcl-2 inhibits apoptosis by regulating the release of cytochrome c and other proteins from mitochondria. Oligomerization of Bax promotes cell death by permeabilizing the outer mitochondrial membrane. In transfected cells and isolated mitochondria, Bcl-2, but not the inactive point mutants Bcl-2-G145A and Bcl-2-V159D, undergoes a conformation change in the mitochondrial membrane in response to apoptotic agonists such as tBid and Bax. A mutant Bcl-2 with two cysteines introduced at positions predicted to result in a disulfide bond that would inhibit the mobility of alpha5-alpha6 helices (Bcl-2-S105C/E152C) was only active in a reducing environment. Thus, Bcl-2 must change the conformation to inhibit tBid-induced oligomerization of integral membrane Bax monomers and small oligomers. The conformationally changed Bcl-2 sequesters the integral membrane form of Bax. If Bax is in excess, apoptosis resumes as Bcl-2 is consumed by the conformational change and in complexes with Bax. Thus, Bcl-2 functions as an inhibitor of mitochondrial permeabilization by changing conformation in the mitochondrial membrane to bind membrane-inserted Bax monomers and prevent productive oligomerization of Bax. 相似文献