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911.
Soeda S Tsuji Y Ochiai T Mishima K Iwasaki K Fujiwara M Yokomatsu T Murano T Shibuya S Shimeno H 《Neurochemistry international》2004,45(5):619-626
Magnesium-dependent neutral sphingomyelinase (N-SMase) present in plasma membranes is an enzyme that can be activated by stress in the form of inflammatory cytokines, serum deprivation, and hypoxia. The design of small molecule N-SMase inhibitors may offer new therapies for the treatment of inflammation, ischemic injury, and cerebral infarction. Recently, we synthesized a series of difluoromethylene analogues (SMAs) of sphingomyelin. We report here the effects of SMAs on the serum/glucose deprivation-induced death of neuronally differentiated pheochromocytoma (PC-12) cells and on cerebral infarction in mice. SMAs inhibited the enhanced N-SMase activity in the serum/glucose-deprived PC-12 cells, and thereby suppressed the apoptotic sequence: ceramide formation, c-Jun N-terminal kinase phosphorylation, caspase-3 activation, and DNA fragmentation in the nuclei. Administration of SMA-7 (10 mg/kg i.v.) with IC50= 3.3 microM to mice whose middle cerebral arteries were occluded reduced significantly the size of the cerebral infarcts, compared to the control mice. These results suggest that N-SMase is a key component of the signaling pathways in cytokine- and other stress-induced cellular responses, and that inhibiting or stopping N-SMase activity is an important strategy to prevent neuron death from ischemia. 相似文献
912.
Mangé A Béranger F Peoc'h K Onodera T Frobert Y Lehmann S 《Biology of the cell / under the auspices of the European Cell Biology Organization》2004,96(2):125-132
It is commonly assumed that the physiological isoform of prion protein, PrP(C), is cleaved during its normal processing between residues 111/112, whereas the pathogenic isoform, PrP(Sc), is cleaved at an alternate site in the octapeptide repeat region around position 90. Here we demonstrated both in cultured cells and in vivo, that PrP(C) is subject to a complex set of post-translational processing with the molecule being cleaved upstream of position 111/112, in the octapeptide repeat region or at position 96. PrP has therefore two main cleavage sites that we decided to name alpha and beta. Cleavage of PrP(C) at these sites leads us to re-evaluate the function of both N- and C-terminus fragments thus generated. 相似文献
913.
Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination 总被引:1,自引:0,他引:1
Watanabe K Tateishi S Kawasuji M Tsurimoto T Inoue H Yamaizumi M 《The EMBO journal》2004,23(19):3886-3896
The DNA replication machinery stalls at damaged sites on templates, but normally restarts by switching to a specialized DNA polymerase(s) that carries out translesion DNA synthesis (TLS). In human cells, DNA polymerase eta (poleta) accumulates at stalling sites as nuclear foci, and is involved in ultraviolet (UV)-induced TLS. Here we show that poleta does not form nuclear foci in RAD18(-/-) cells after UV irradiation. Both Rad18 and Rad6 are required for poleta focus formation. In wild-type cells, UV irradiation induces relocalization of Rad18 in the nucleus, thereby stimulating colocalization with proliferating cell nuclear antigen (PCNA), and Rad18/Rad6-dependent PCNA monoubiquitination. Purified Rad18 and Rad6B monoubiquitinate PCNA in vitro. Rad18 associates with poleta constitutively through domains on their C-terminal regions, and this complex accumulates at the foci after UV irradiation. Furthermore, poleta interacts preferentially with monoubiquitinated PCNA, but poldelta does not. These results suggest that Rad18 is crucial for recruitment of poleta to the damaged site through protein-protein interaction and PCNA monoubiquitination. 相似文献
914.
Komatsu M Chiba T Tatsumi K Iemura S Tanida I Okazaki N Ueno T Kominami E Natsume T Tanaka K 《The EMBO journal》2004,23(9):1977-1986
Several studies have addressed the importance of various ubiquitin-like (UBL) post-translational modifiers. These UBLs are covalently linked to most, if not all, target protein(s) through an enzymatic cascade analogous to ubiquitylation, consisting of E1 (activating), E2 (conjugating), and E3 (ligating) enzymes. In this report, we describe the identification of a novel ubiquitin-fold modifier 1 (Ufm1) with a molecular mass of 9.1 kDa, displaying apparently similar tertiary structure, although lacking obvious sequence identity, to ubiquitin. Ufm1 is first cleaved at the C-terminus to expose its conserved Gly residue. This Gly residue is essential for its subsequent conjugating reactions. The C-terminally processed Ufm1 is activated by a novel E1-like enzyme, Uba5, by forming a high-energy thioester bond. Activated Ufm1 is then transferred to its cognate E2-like enzyme, Ufc1, in a similar thioester linkage. Ufm1 forms several complexes in HEK293 cells and mouse tissues, revealing that it conjugates to the target proteins. Ufm1, Uba5, and Ufc1 are all conserved in metazoa and plants but not in yeast, suggesting its potential roles in various multicellular organisms. 相似文献
915.
Tatsumi R Seio K Fujio M Katayama J Horikawa T Hashimoto K Tanaka H 《Bioorganic & medicinal chemistry letters》2004,14(14):3781-3784
A series of 3-substituted 1-azabicyclo[2.2.2]octanes was discovered as the alpha7 nicotinic acetylcholine (alpha7) receptor agonists. It was found that (+)-3-[2-(benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane (+)-15b has potent agonistic activity for the alpha7 receptor. 相似文献
916.
Kitayama T Iwabuchi R Minagawa S Shiomi F Cappiello J Sawada S Utsumi R Okamoto T 《Bioorganic & medicinal chemistry letters》2004,14(23):5943-5946
Zerumbone ring-opening derivative, 4 (10E/10Z=3/2), inhibited autophosphorylation of the essential histidine-kinase YycG existing in Bacillus subtilis constituting a two-component system (TCS). Generation of 4E-form could be regulated chemically using the difference from the ring-opening reactivity of the precursor forming of 4 and pure 4E was isolated. The stereoisomer, 4E, showed main inhibition activity of autophosphorylation of YycG (IC(50)=63.5 microM). 相似文献
917.
Kobori A Murase T Suda H Saito I Nakatani K 《Bioorganic & medicinal chemistry letters》2004,14(13):3431-3433
We have demonstrated that aromatic heterocycles having hydrogen-bonding surfaces complementary to those of nucleotide bases are effective molecular elements for the binding to single nucleotide bulges and base mismatches. We here report that a new molecule, 2-ureidoquinoline having an alignment of hydrogen-bonding groups in the order of acceptor-donor-donor stabilizes single cytosine and thymine bulges in duplex DNAs. Furthermore, a dimeric form of 2-ureidoquinoline stabilizes cytosine-cytosine and cytosine-thymine mismatches. 相似文献
918.
Tailed calix[4]resorcarene macrocycle (tail=undecyl) can be used as a platform to assemble four glycosaminoglycan polysaccharide chains to give a new type of proteoglycan mimics. A tetra(chondroitin sulfate) derivative thus obtained from the reaction of macrocyclic octaamine and chondroitin sulfate lactone is readily immobilized on a tissue culture plastic (polystyrene) plate and inhibits fibronectin-mediated adhesion of BHK (baby hamster kidney) cells thereon remarkably strongly with 50% inhibition occurring at a 10 ng/mL or 40 pM concentration range. 相似文献
919.
Tanaka M Sagawa S Hoshi J Shimoma F Matsuda I Sakoda K Sasase T Shindo M Inaba T 《Bioorganic & medicinal chemistry letters》2004,14(20):5171-5174
We report herein synthesis of PKCbeta-selective inhibitors possessing the novel pharmacophore of anilino-monoindolylmaleimide. Several compounds of this series exhibited IC50's as low as 50 nM against human PKCbeta2. One of the most potent compounds, 6l, inhibited PKCbeta1 and PKCbeta2 with IC50 of 21 and 5 nM, respectively, and exhibited selectivity of more than 60-fold in favor of PKCbeta2 relative to other PKC isozymes (PKCalpha, PKCgamma, and PKCepsilon). 相似文献
920.
Inoue M Zhai H Sakazaki H Furuyama H Fukuyama Y Hirama M 《Bioorganic & medicinal chemistry letters》2004,14(3):663-665
TMC-95A has been characterized as a potent proteasome inhibitor that binds to enzymes non-covalently at low nanomolar concentrations. Herein, the neuritogenic activity of TMC-95A in PC12 rat pheochromocytoma cells is reported for the first time. TMC-95A induced a positive neurite initiation of PC12 cells at concentration ranging from 1 to 20 microM. 相似文献