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971.
Zhao Y Haccard O Wang R Yu J Kuang J Jessus C Goldberg ML 《Molecular biology of the cell》2008,19(4):1317-1327
We previously reported that immunodepletion of Greatwall kinase prevents Xenopus egg extracts from entering or maintaining M phase due to the accumulation of inhibitory phosphorylations on Thr14 and Tyr15 of Cdc2. M phase-promoting factor (MPF) in turn activates Greatwall, implying that Greatwall participates in an MPF autoregulatory loop. We show here that activated Greatwall both accelerates the mitotic G2/M transition in cycling egg extracts and induces meiotic maturation in G2-arrested Xenopus oocytes in the absence of progesterone. Activated Greatwall can induce phosphorylations of Cdc25 in the absence of the activity of Cdc2, Plx1 (Xenopus Polo-like kinase) or mitogen-activated protein kinase, or in the presence of an activator of protein kinase A that normally blocks mitotic entry. The effects of active Greatwall mimic in many respects those associated with addition of the phosphatase inhibitor okadaic acid (OA); moreover, OA allows cycling extracts to enter M phase in the absence of Greatwall. Taken together, these findings support a model in which Greatwall negatively regulates a crucial phosphatase that inhibits Cdc25 activation and M phase induction. 相似文献
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973.
Romy F.J. Janser Ranjith K. Meka Zack E. Bryant Enoch A. Adogla Elizabeth K. Vogel Jaimie L. Wharton Cynthia M. Tilley Catherine N. Kaminski Seth L. Ferrey Severine Van slambrouck Wim F.A. Steelant Ingo Janser 《Bioorganic & medicinal chemistry letters》2010,20(6):1848-1850
A series of ethacrynic acid analogues, lacking the α,β-unsaturated carbonyl unit, was synthesized and subsequently evaluated for their ability to inhibit the migration of human breast cancer cells, MCF-7/AZ. Several of the analogues were already active in the low micromolar range, whereas ethacrynic acid itself shows no potential to inhibit the migration of these cancer cells. Preliminary studies show that the presence of one or more methoxy groups at the phenyl ring of ethacrynic acid is important in order for the ethacrynic acid analogues to demonstrate an inhibitory effect on the migration. 相似文献
974.
Etienne Paux Sébastien Faure Frédéric Choulet Delphine Roger Valérie Gauthier Jean‐Pierre Martinant Pierre Sourdille François Balfourier Marie‐Christine Le Paslier Aurélie Chauveau Mehmet Cakir Béatrice Gandon Catherine Feuillet 《Plant biotechnology journal》2010,8(2):196-210
In wheat, the deployment of marker‐assisted selection has long been hampered by the lack of markers compatible with high‐throughput cost‐effective genotyping techniques. Recently, insertion site‐based polymorphism (ISBP) markers have appeared as very powerful new tools for genomics and genetic studies in hexaploid wheat. To demonstrate their possible use in wheat breeding programmes, we assessed their potential to meet the five main requirements for utilization in MAS: flexible and high‐throughput detection methods, low quantity and quality of DNA required, low cost per assay, tight link to target loci and high level of polymorphism in breeding material. Toward this aim, we developed a programme, IsbpFinder, for the automated design of ISBP markers and adapted three detection methods (melting curve analysis, SNaPshot® Multiplex System and Illumina BeadArray technology) for high throughput and flexible detection of ISBP or ISBP‐derived SNP markers. We demonstrate that the high level of polymorphism of the ISBPs combined with cost‐effective genotyping methods can be used to efficiently saturate genetic maps, discriminate between elite cultivars, and design tightly linked diagnostic markers for virtually all target loci in the wheat genome. All together, our results suggest that ISBP markers have the potential to lead to a breakthrough in wheat marker‐assisted selection. 相似文献
975.
A classical voltage-sensitive channel is tension sensitive—the kinetics of Shaker and S3–S4 linker deletion mutants change with membrane stretch (Tabarean, I.V., and C.E. Morris. 2002. Biophys. J. 82:2982–2994.). Does stretch distort the channel protein, producing novel channel states, or, more interestingly, are existing transitions inherently tension sensitive? We examined stretch and voltage dependence of mutant 5aa, whose ultra-simple activation (Gonzalez, C., E. Rosenman, F. Bezanilla, O. Alvarez, and R. Latorre. 2000. J. Gen. Physiol. 115:193–208.) and temporally matched activation and slow inactivation were ideal for these studies. We focused on macroscopic patch current parameters related to elementary channel transitions: maximum slope and delay of current rise, and time constant of current decline. Stretch altered the magnitude of these parameters, but not, or minimally, their voltage dependence. Maximum slope and delay versus voltage with and without stretch as well as current rising phases were well described by expressions derived for an irreversible four-step activation model, indicating there is no separate stretch-activated opening pathway. This model, with slow inactivation added, explains most of our data. From this we infer that the voltage-dependent activation path is inherently stretch sensitive. Simulated currents for schemes with additional activation steps were compared against datasets; this showed that generally, additional complexity was not called for. Because the voltage sensitivities of activation and inactivation differ, it was not possible to substitute depolarization for stretch so as to produce the same overall PO time course. What we found, however, was that at a given voltage, stretch-accelerated current rise and decline almost identically—normalized current traces with and without stretch could be matched by a rescaling of time. Rate-limitation of the current falling phase by activation was ruled out. We hypothesize, therefore, that stretch-induced bilayer decompression facilitates an in-plane expansion of the protein in both activation and inactivation. Dynamic structural models of this class of channels will need to take into account the inherent mechanosensitivity of voltage-dependent gating. 相似文献
976.
Abdulhussein R McFadden C Fuentes-Prior P Vogel WF 《The Journal of biological chemistry》2004,279(30):31462-31470
Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are tyrosine kinase receptors activated by triple-helical collagens. Aberrant expression and signaling of these receptors have been implicated in several human diseases linked to accelerated matrix degradation and remodeling including tumor invasion, atherosclerosis and liver fibrosis. The objective of this study is to characterize the collagen-binding sites in the discoidin domains of DDR1 and DDR2 at a molecular level. We expressed glutathione S-transferase fusion proteins containing the discoidin and extracellular domains of DDR1 and DDR2 in insect cells and subjected them to a solid-phase collagen-binding assay. We found high affinity binding of the DDR extracellular domains to immobilized type I collagen and confirmed the discoidin-collagen interaction with an enzyme-linked immunosorbent assay-based read-out. Furthermore, we created a three-dimensional model of the DDR1 discoidin domain based on the related domains of blood coagulation factors V and VIII. This model predicts the presence of four neighboring, surface-exposed loops that are topologically equivalent to a major phospholipid-binding site in factors V and VIII. To test the involvement of these loops in collagen binding, we mutated individual amino acid residues to alanine or deleted short sequence stretches within these loops. We found that several residues within loop 1 (Ser-52-Thr-57) and loop 3 (Arg-105-Lys-112) as well as Ser-175 in loop 4 are critically involved in collagen binding. Our structure-function analysis of the DDR discoidin domains provides new insights into this non-integrin-mediated collagen-signaling mechanism and may ultimately lead to the design of small molecule inhibitors that interfere with aberrant DDR function. 相似文献
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979.