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101.
Ana Guarner Cristina Manjón Kevin Edwards Hermann Steller Magali Suzanne Ernesto Sánchez-Herrero 《Developmental biology》2014
The development of the Drosophila leg is a good model to study processes of pattern formation, cell death and segmentation. Such processes require the coordinate activity of different genes and signaling pathways that progressively subdivide the leg territory into smaller domains. One of the main pathways needed for leg development is the Notch pathway, required for determining the proximo-distal axis of the leg and for the formation of the joints that separate different leg segments. The mechanisms required to coordinate such events are largely unknown. We describe here that the zinc finger homeodomain-2 (zfh-2) gene is highly expressed in cells that will form the leg joints and needed to establish a correct size and pattern in the distal leg. There is an early requirement of zfh-2 to establish the correct proximo-distal axis, but zfh-2 is also needed at late third instar to form the joint between the fourth and fifth tarsal segments. The expression of zfh-2 requires Notch activity but zfh-2 is necessary, in turn, to activate Notch targets such as Enhancer of split and big brain. zfh-2 is controlled by the Drosophila activator protein 2 gene and regulates the late expression of tarsal-less. In the absence of zfh-2 many cells ectopically express the pro-apoptotic gene head involution defective, activate caspase-3 and are positive for acridine orange, indicating they undergo apoptosis. Our results demonstrate the key role of zfh-2 in the control of cell death and Notch signaling during leg development. 相似文献
102.
Proteomic analysis of parkin knockout mice: alterations in energy metabolism, protein handling and synaptic function 总被引:8,自引:0,他引:8
Parkin knockout (KO) mice show behavioural and biochemical changes that reproduce some of the presymptomatic aspects of Parkinson's disease, in the absence of neuronal degeneration. To provide insight into the pathogenic mechanisms underlying the preclinical stages of parkin-related parkinsonism, we searched for possible changes in the brain proteome of parkin KO mice by means of fluorescence two-dimensional difference gel electrophoresis and mass spectrometry. We identified 87 proteins that differed in abundance between wild-type and parkin KO mice by at least 45%. A high proportion of these proteins were related to energy metabolism. The levels of several proteins involved in detoxification, stress-related chaperones and components of the ubiquitin-proteasome pathway were also altered. These differences might reflect adaptive mechanisms aimed at compensating for the presence of reactive oxygen species and the accumulation of damaged proteins in parkin KO mice. Furthermore, the up-regulation of several members of the membrane-associated guanylate kinase family of synaptic scaffold proteins and several septins, including the Parkin substrate cell division control related protein 1 (CDCRel-1), may contribute to the abnormalities in neurotransmitter release previously observed in parkin KO mice. This study provides clues into possible compensatory mechanisms that protect dopaminergic neurones from death in parkin KO mice and may help us understand the preclinical deficits observed in parkin-related parkinsonism. 相似文献
103.
We assessed the effects of intracrystalline urinary proteins on the ability of Type II Madin-Darby canine kidney (MDCK-II) cells to bind and degrade calcium oxalate monohydrate (COM) crystals. Binding of [14C]-labelled inorganic crystals (iCOM), and COM crystals precipitated from centrifuged and filtered (CF) or ultrafiltered (UF) human urine was quantified by radioactive analysis. SDS-PAGE confirmed the presence of intracrystalline proteins > 10 kDa in CF crystals and their absence from UF crystals. Morphological effects were assessed qualitatively by field emission scanning electron microscopy. iCOM crystals bound rapidly and extensively and were resistant to degradation. Binding of CF crystals was weaker than UF crystals, and both had markedly less affinity than iCOM. CF and UF crystals were extensively degraded within 90 min, the effect being more pronounced with CF. These results support our hypothesis that intracrystalline proteins protect against urolithiasis by facilitating intracellular proteolytic digestion and destruction of crystals phagocytosed by urothelial cells. 相似文献
104.
Mathieu M Debousker G Vincent S Viviani F Bamas-Jacques N Mikol V 《The Journal of biological chemistry》2005,280(19):18916-18922
In some bacteria, such as Escherichia coli, the addition of L-glutamate to dihydropteroate (dihydrofolate synthetase activity) and the subsequent additions of L-glutamate to tetrahydrofolate (folylpolyglutamate synthetase (FPGS) activity) are catalyzed by the same enzyme, FolC. The crystal structure of E. coli FolC is described in this paper. It showed strong similarities to that of the FPGS enzyme of Lactobacillus casei within the ATP binding site and the catalytic site, as do all other members of the Mur synthethase superfamily. FolC structure revealed an unexpected dihydropteroate binding site very different from the folate site identified previously in the FPGS structure. The relevance of this site is exemplified by the presence of phosphorylated dihydropteroate, a reaction intermediate in the DHFS reaction. L. casei FPGS is considered a relevant model for human FPGS. As such, the presence of a folate binding site in E. coli FolC, which is different from the one seen in FPGS enzymes, provides avenues for the design of specific inhibitors of this enzyme in antimicrobial therapy. 相似文献
105.
Wood DR Nye JS Lamb NJ Fernandez A Kitzmann M 《The Journal of biological chemistry》2005,280(8):6663-6668
Mutations in genes encoding presenilins (PS1 and PS2) are responsible for the majority of early onset familial Alzheimer's disease. PS, a critical component of gamma-secretase, is responsible for the intramembranous cleavage of amyloid precursor protein and Notch. Other physiological functions have been assigned to PS without any clear identification of the mechanisms underlying these multiple biological roles. The early embryonic lethality of PS1 and PS2 double knock-out (PS1/2 null) mice prevents the evaluation of physiological roles of PS. To investigate new functions for presenilins, we performed a proteomic approach by using cells derived from PS1/2 null blastocysts and wild type controls. We identified a presenilin-dependent cell-surface binding of albumin. Binding of albumin depends on intact caveolae on the cellular surface. Abnormal caveolin 1 localization in PS1/2 null cells was associated with a loss of caveolae and an absence of caveolin 1 expression within lipid rafts. Expressing PS1 or PS2 but not the intracellular form of Notch1 in PS1/2 null cells restored normal caveolin 1 localization, demonstrating that presenilins are required for the subcellular trafficking of caveolin 1 independently from Notch activity. Despite an expression of both caveolin 1 and PS1 within lipid raft-enriched fractions after sucrose density centrifugation in wild type cells, no direct interaction between these two proteins was detected, implying that presenilins affect caveolin 1 trafficking in an indirect manner. We conclude that presenilins are required for caveolae formation by controlling transport of intracellular caveolin 1 to the plasma membrane. 相似文献
106.
107.
Berthouze M Ayoub M Russo O Rivail L Sicsic S Fischmeister R Berque-Bestel I Jockers R Lezoualc'h F 《FEBS letters》2005,579(14):2973-2980
Serotonin 5-HT4 receptor isoforms are G protein-coupled receptors (GPCRs) with distinct pharmacological properties and may represent a valuable target for the treatment of many human disorders. Here, we have explored the process of dimerization of human 5-HT4 receptor (h5-HT4R) by means of co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Constitutive h5-HT4(d)R dimer was observed in living cells and membrane preparation of CHO and HEK293 cells. 5-HT4R ligands did not influence the constitutive energy transfer of the h5-HT4(d)R splice variant in intact cells and isolated plasma membranes. In addition, we found that h5-HT4(d)R and h5-HT4(g)R which structurally differ in the length of their C-terminal tails were able to form constitutive heterodimers independently of their activation state. Finally, we found that coexpression of h5-HT4R and beta2-adrenergic receptor (beta2AR) led to their heterodimerization. Given the large number of h5-HT4R isoforms which are coexpressed in a same tissue, our results points out the complexity by which this 5-HTR sub-type mediates its biological effects. 相似文献
108.
Pizzut-Serin S Potocki-Véronèse G van der Veen BA Albenne C Monsan P Remaud-Simeon M 《FEBS letters》2005,579(6):1405-1410
The BLAST search for amylosucrases has yielded several gene sequences of putative amylosucrases, however, with various questionable annotations. The putative encoded proteins share 32-48% identity with Neisseria polysaccharea amylosucrase (AS) and contain several amino acid residues proposed to be involved in AS specificity. First, the B-domains of the putative proteins and AS are highly similar. In addition, they also reveal additional residues between putative beta-strand 7 and alpha-helix 7 which could correspond to the AS B'-domain, which turns the active site into a deep pocket. Finally, conserved Asp and Arg residues could form a salt bridge similar to that found in AS, which is responsible for the glucosyl unit transfer specificity. Among these found genes, locus NP_294657.1 (dras) identified in the Deinococcus radiodurans genome was initially annotated as an alpha-amylase encoding gene. The putative encoded protein (DRAS) shares 42% identity with N. polysaccharea AS. To investigate the activity of this protein, gene NP_294657.1 was cloned and expressed in Escherichia coli. When acting on sucrose, the pure recombinant enzyme was shown to catalyse insoluble amylose polymer synthesis accompanied by side-reactions (sucrose hydrolysis, sucrose isomer and soluble maltooligosaccharide formation). Kinetic analyses further showed that DRAS follows a non-Michaelian behaviour toward sucrose substrate and is activated by glycogen, as is AS. This demonstrates that gene NP_294657.1 encodes an amylosucrase. 相似文献
109.
A disaccharide portion of the A-side chain of the rhamnogalacturonan II oligosaccharide has been prepared. Glycosylation of methyl (methyl 3,4-O-isopropylidene-alpha-D-galactopyranosid)uronate with p-tolyl 2,3-di-O-acetyl-3-C-(benzyloxymethyl)-1-thio-alpha/beta-D-erythrofuranoside was carried out using N-iodosuccinimide as promoter and silver trifluoromethanesulfonate as catalyst. Removal of the protecting groups gave the beta-d-Apif-(1-->2)-alpha-D-GalpA-OMe disaccharide. 相似文献
110.
DNA replication is a complex mechanism that functions due to the coordinated interplay of many factors. In the last few years, numerous studies have suggested that DNA replication factors are closely implicated in several DNA transaction events that maintain the integrity of the genome. Therefore, DNA replication fork factors have to be considered as part of a general process that aims to protect and replicate the genome in order to allow correct functioning of a cell and its eventual daughter cells. This is illustrated by the numerous factors that have a well-defined function at the DNA replication fork, but also play crucial roles in different DNA repair pathways such as base excision repair, nucleotide excision repair, double-strand break repair, and mismatch repair. Moreover, several of the replisome proteins have also been shown to be essential in sensing and transducing DNA damages through the checkpoint cascade pathways, including the recently characterised alternative clamps and clamp-loaders. In this review we present DNA replication factors that are involved in different DNA transaction and checkpoint regulation pathways, with emphasis on the link between DNA replication and maintenance of genomic stability. 相似文献