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排序方式: 共有230条查询结果,搜索用时 17 毫秒
51.
5-azacytidine alters TGF-beta and BMP signaling and induces maturation in articular chondrocytes 总被引:2,自引:0,他引:2
Zuscik MJ Baden JF Wu Q Sheu TJ Schwarz EM Drissi H O'Keefe RJ Puzas JE Rosier RN 《Journal of cellular biochemistry》2004,92(2):316-331
Maintenance of the articular surface depends on the function of articular chondrocytes (ACs) which produce matrix and are constrained from undergoing the maturation program seen in growth plate chondrocytes. Only during pathologic conditions, such as in osteoarthritis, are maturational constraints lost causing recapitulation of the process that occurs during endochondral ossification. With the aim of establishing a model to identify regulatory mechanisms that suppress AC hypertrophy, we examined the capability of 5-azacytidine (Aza) to have an impact on the maturational program of these cells. Primary ACs do not spontaneously express markers of maturation and are refractory to treatment by factors that normally regulate chondrocyte maturation. However, following exposure to Aza, ACs (i) were induced to express type X collagen (colX), Indian hedgehog, and alkaline phosphatase and (ii) showed altered colX and AP expression in response to bone morphogenetic protein-2 (BMP-2), transforming growth factor-beta (TGF-beta), and parathyroid hormone-related protein (PTHrP). Since Aza unmasked responsiveness of ACs to BMP-2 and TGF-beta, we examined the effect of Aza treatment on signaling via these pathways by assessing the expression of the TGF-beta Smads (2 and 3), the BMP-2 Smads (1 and 5), and the Smad2 and 3-degrading ubiquitin E3 ligase Smurf2. Aza-treated ACs displayed less Smad2 and 3 and increased Smad1, 5, and Smurf2 protein and showed a loss of TGF-beta signaling on the P3TP-luciferase reporter. Suggesting that Aza-induction of Smurf2 may be responsible for the loss of Smad2 and 3 protein via this pathway, immunoprecipitation and metabolic labeling experiments confirmed that Aza accelerated the ubiquitination and degradation of these targets. Overall, Aza-treated ACs represent a novel model for the study of mechanisms that regulate maturational potential of articular cartilage, with the data suggesting that maturation of these cells may be due to up-regulation of Smad1 and 5 coupled with a Smurf2-dependent degradation of Smad2 and 3 and loss of TGF-beta signaling. 相似文献
52.
Wang M Ng KK Cherney MM Chan L Yannopoulos CG Bedard J Morin N Nguyen-Ba N Alaoui-Ismaili MH Bethell RC James MN 《The Journal of biological chemistry》2003,278(11):9489-9495
X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNA-dependent RNA polymerase have been determined to 2.0 and 2.9 A resolution. These noncompetitive inhibitors bind to the same site on the protein, approximately 35 A from the active site. The common features of binding include a large hydrophobic region and two hydrogen bonds between both oxygen atoms of a carboxylate group on the inhibitor and two main chain amide nitrogen atoms of Ser(476) and Tyr(477) on NS5B. The inhibitor-binding site lies at the base of the thumb domain, near its interface with the C-terminal extension of NS5B. The location of this inhibitor-binding site suggests that the binding of these inhibitors interferes with a conformational change essential for the activity of the polymerase. 相似文献
53.
Rochdi MD Watier V La Madeleine C Nakata H Kozasa T Parent JL 《The Journal of biological chemistry》2002,277(43):40751-40759
Although ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is a PDZ domain-containing protein known to bind to various channels, receptors, cytoskeletal elements, and cytoplasmic proteins, there is still very little evidence for a role of EBP50 in the regulation of receptor signal transduction. In this report, we show that EBP50 inhibits the phospholipase C (PLC)-beta-mediated inositol phosphate production of a Galpha(q)-coupled receptor as well as PLC-beta activation by the constitutively active Galpha(q)-R183C mutant. Coimmunoprecipitation experiments revealed that EBP50 interacts with Galpha(q) and to a greater extent with Galpha(q)-R183C. Agonist stimulation of the thromboxane A(2) receptor (TP receptor) resulted in an increased interaction between EBP50 and Galpha(q), suggesting that EBP50 preferentially interacts with activated Galpha(q). We also demonstrate that EBP50 inhibits Galpha(q) signaling by preventing the interaction between Galpha(q) and the TP receptor and between activated Galpha(q) and PLC-beta1. Investigation of the EBP50 regions involved in Galpha(q) binding indicated that its two PDZ domains are responsible for this interaction. This study constitutes the first demonstration of an interaction between a G protein alpha subunit and another protein through a PDZ domain, with broad implications in the regulation of diverse physiological systems. 相似文献
54.
Ethylene-regulated gene expression in tomato fruit: characterization of novel ethylene-responsive and ripening-related genes isolated by differential display 总被引:29,自引:5,他引:24
55.
M A Phelouzat F Lawrence L Moulay C Borot J Schaeverbeke M Schaeverbeke M Robert-Gero 《Experimental parasitology》1992,74(2):177-187
Sinefungin, an antifungal and antiparasitic nucleoside antibiotic, is a very potent antileishmanial agent in vitro and in vivo (Bachrach et al. 1980, FEBS Letters 121, 287-291; Neal et al. 1985, Transactions of the Royal Society of Tropical Medicine and Hygiene 79, 85-122). It was previously shown that this molecule is a competitive inhibitor of AdoMet for transmethylases (Paolantonacci et al. 1986, Molecular and Biochemical Parasitology 21, 47-54; Avila et al. 1987, Molecular and Biochemical Parasitology 26, 69-76) and that it induces shape changes of Leishmania donovani promastigotes as observed by light microscopy (Lawrence and Robert-Gero 1990; Bulletin de la Societé Fran?aise de Parasitologie 8, 13-18). In the present work the effect of the antibiotic on the ultrastructure was analyzed by electron microscopy. The main changes induced at sublethal concentrations (0.26 microM sinefungin for 16 hr) were progressive rounding, decreased motility, enlargement of the flagellar pocket, and shortening and loss of the external part of the flagellum. The comparison with control cells showed shorter Golgi saccules and fragmentation of the trans-Golgi network into vesicles, indicating a stimulated Golgi apparatus activity. This result, associated with the enlarged flagellar pocket, suggests an unbalanced cytoplasmic exchange between exocytosis and endocytosis. These effects are quite different from those induced by tunicamycin (Dagger et al. 1984, Biology of the Cell 50; 173-180) or paromomycin. In addition, other nucleoside and nonnucleoside growth inhibitors failed to induce similar changes. AdoMet antagonized the sinefungin-induced shape changes and ultrastructural modifications but had no effect with respect to other growth inhibitors. This suggests that the sinefungin activity at the cellular level is specifically related to competition with AdoMet. A comparative study of N-methylation and carboxylmethylation of proteins in sinefungin-treated promastigotes showed that the antibiotic preferentially inhibits the latter, catalyzed by protein-O-methyltransferases. These enzymes are known to regulate the function of various proteins involved in secretion. Overall the results suggest that one of the main targets of sinefungin in exponentially growing cells is the protein carboxylmethylation involved in membrane transport. 相似文献
56.
57.
Vergne F Bernardelli P Lorthiois E Pham N Proust E Oliveira C Mafroud AK Ducrot P Wrigglesworth R Berlioz-Seux F Coleon F Chevalier E Moreau F Idrissi M Tertre A Descours A Berna P Li M 《Bioorganic & medicinal chemistry letters》2004,14(18):4615-4621
The synthesis and optimization of pharmacokinetic parameters of structurally novel small PDE7 inhibitors is discussed. 相似文献
58.
Bernardelli P Lorthiois E Vergne F Oliveira C Mafroud AK Proust E Pham N Ducrot P Moreau F Idrissi M Tertre A Bertin B Coupe M Chevalier E Descours A Berlioz-Seux F Berna P Li M 《Bioorganic & medicinal chemistry letters》2004,14(18):4627-4631
The optimization of 5,8-disubstituted spirocyclohexane-quinazolinones into potent, selective, soluble PDE7 inhibitors with acceptable in vivo pharmacokinetic parameters is presented. 相似文献
59.
Dong Y Drissi H Chen M Chen D Zuscik MJ Schwarz EM O'Keefe RJ 《Journal of cellular biochemistry》2005,95(5):1057-1068
Wnt proteins are expressed during limb morphogenesis, yet their role and mechanism of action remains unclear during long bone growth. Wnt expression, effects and modulation of signaling events by BMP and transforming growth factor-beta (TGF-beta) were evaluated in chick embryonic chondrocytes. Chondrocyte cell cultures underwent spontaneous maturation with increased expression of colX and this was associated with an increase in the expression of multiple Wnts, including Wnt 4, 5a, 8c, and 9a. Both parathyroid hormone related peptide (PTHrP) and TGF-beta inhibited colX, but had disparate effects on Wnt expression. While TGF-beta strongly inhibited all Wnts, PTHrP did not inhibit either Wnt8c or Wnt9a and had lesser effects on the expression of the other Wnts. BMP-2 induced colX expression, and also markedly increased Wnt8c expression. Overexpression of beta-catenin and/or T cell factor (TCF)-4 also induced the type X collagen promoter. Overexpression of Wnt8c induced maturation, as did overexpression of beta-catenin. The Wnt8c/beta-catenin maturational effects were enhanced by BMP-2 and inhibited by TGF-beta. TGF-beta also inhibited activation of the Topflash reporter by beta-catenin, suggesting a direct inhibitory effect since the Topflash reporter contains only beta-catenin binding sequences. In turn beta-catenin inhibited activation of the p3TP-Luc reporter by TGF-beta, although the effect was partial. Thus, Wnt/beta-catenin signaling is a critical regulator of the rate of chondrocyte differentiation. Moreover, this pathway is modulated by members of the TGF-beta family and demonstrates the highly integrated nature of signals controlling endochondral ossification. 相似文献
60.
Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein. 总被引:9,自引:0,他引:9
Bernard Masri Hicham Lahlou Honoré Mazarguil Bernard Knibiehler Yves Audigier 《Biochemical and biophysical research communications》2002,290(1):539-545
We report here that apelin (65-77) induces activation of extracellular-regulated kinases (ERKs) in Chinese hamster ovary (CHO) cells expressing the msr/apj receptor. This concentration-dependent activation was transient, peaking at 5 min. Pretreatment of CHO cells with pertussis toxin fully abrogated ERK phosphorylation, whereas overexpression of the beta-adrenergic receptor kinase-1 C-terminal fragment did not alter ERK activation. Transfection with a dominant-negative mutant of Ras was without effect on ERK activation, whereas an inhibitor of many protein kinase C isoforms, GF109203X, strongly decreased it. These results demonstrate that stimulation of the murine msr/apj receptor promotes ERK activation via the alpha subunit of a pertussis toxin-sensitive protein in a Ras-independent pathway. 相似文献