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71.
Leucyl-tRNA synthetase controls TORC1 via the EGO complex 总被引:1,自引:0,他引:1
Bonfils G Jaquenoud M Bontron S Ostrowicz C Ungermann C De Virgilio C 《Molecular cell》2012,46(1):105-110
The target of rapamycin complex 1 (TORC1) is an essential regulator of eukaryotic cell growth that responds to growth factors, energy levels, and amino acids. The mechanisms through which the preeminent amino acid leucine signals to the TORC1-regulatory Rag GTPases, which activate TORC1 within the yeast EGO complex (EGOC) or the structurally related mammalian Rag-Ragulator complex, remain elusive. We find that the leucyl-tRNA synthetase (LeuRS) Cdc60 interacts with the Rag GTPase Gtr1 of the EGOC in a leucine-dependent manner. This interaction is necessary and sufficient to mediate leucine signaling to TORC1 and is disrupted by the?engagement of Cdc60 in editing mischarged tRNA(Leu). Thus, the EGOC-TORC1 signaling module samples, via the LeuRS-intrinsic editing domain, the fidelity of tRNA(Leu) aminoacylation as a proxy for leucine availability. 相似文献
72.
van Noort JM Bsibsi M Nacken P Gerritsen WH Amor S 《The international journal of biochemistry & cell biology》2012,44(10):1670-1679
There is now compelling evidence that members of the family of small heat shock proteins (HSP) can be secreted by a variety of different types of cells. Secretion of small HSP may at times represent altruistic delivery of supporting and stabilizing factors from one cell to another. A probably more general effect of extracellular small HSP, however, is exerted by their ability to activate macrophages and macrophage-like cells. When doing so, small HSP induce an immune-regulatory state of activation, stimulating macrophages to suppress inflammation. For this reason, small HSP deserve consideration as broadly applicable therapeutic agents for inflammatory disorders. In one particular case, however, adaptive immune responses to the small HSP itself may subvert the protective quality of the innate immune response it triggers. This situation only applies to alpha B-crystallin, and is unique for humans as well. In this special case, local concentrations of alpha B-crystallin determine the balance between protective innate responses and destructive adaptive responses, the latter of which are held responsible for the development of multiple sclerosis lesions. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. 相似文献
73.
Luz Marina Acevedo Irene Londono Malika Oubaha Lucian Ghitescu Moise Bendayan 《The journal of histochemistry and cytochemistry》2008,56(6):605-614
Aging and diabetes are associated with exacerbated expression of adhesion molecules. Given their importance in endothelial dysfunction and their possible involvement in the alteration of glomerular permeability occurring in diabetes, we have evaluated expression of the sialomucin-type adhesion molecule CD34 in renal glomerular cells of normal and diabetic animals at two different ages by colloidal gold immunocytochemistry and immunoblotting. CD34 labeling was mostly assigned to the plasma membranes of glomerular endothelium and mesangial processes. Podocyte membranes were also labeled, but to a lesser degree. Short- and long-term diabetes triggers a substantial increase in immunogold labeling for CD34 in renal tissues compared with young normoglycemic animals. However, the level of labeling in old diabetic and healthy control rats is similar, suggesting that the effect of diabetes and aging on CD34 expression is similar but not synergistic. Western blotting of isolated glomerular fractions corroborated immunocytochemical results. Increased expression of CD34 may reflect its involvement in the pathogenesis of glomerular alterations related to age and diabetes. Alterations present in early diabetes, resembling those occurring with age, strengthen the concept that diabetes is an accelerated form of aging. 相似文献
74.
Since it has been proven these last years that the introduction of a heteroatom in the steroidal moiety could have a biological impact, there has been progress in the field of thiasteroids. The recent development in the partial and total syntheses of thiasteroids are herein described. 相似文献
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76.
Beautrait A Leroux V Chavent M Ghemtio L Devignes MD Smaïl-Tabbone M Cai W Shao X Moreau G Bladon P Yao J Maigret B 《Journal of molecular modeling》2008,14(2):135-148
Numerous methods are available for use as part of a virtual screening strategy but, as yet, no single method is able to guarantee
both a level of confidence comparable to experimental screening and a level of computing efficiency that could drastically
cut the costs of early phase drug discovery campaigns. Here, we present VSM-G (virtual screening manager for computational
grids), a virtual screening platform that combines several structure-based drug design tools. VSM-G aims to be as user-friendly
as possible while retaining enough flexibility to accommodate other in silico techniques as they are developed. In order to
illustrate VSM-G concepts, we present a proof-of-concept study of a fast geometrical matching method based on spherical harmonics
expansions surfaces. This technique is implemented in VSM-G as the first module of a multiple-step sequence tailored for high-throughput
experiments. We show that, using this protocol, notable enrichment of the input molecular database can be achieved against
a specific target, here the liver-X nuclear receptor. The benefits, limitations and applicability of the VSM-G approach are
discussed. Possible improvements of both the geometrical matching technique and its implementation within VSM-G are suggested.
Figure Basic principle of the virtual screening funnel process.
相似文献
Bernard MaigretEmail: |
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78.
Boukhelifa M Moza M Johansson T Rachlin A Parast M Huttelmaier S Roy P Jockusch BM Carpen O Karlsson R Otey CA 《The FEBS journal》2006,273(1):26-33
Palladin is an actin-associated protein that has been suggested to play critical roles in establishing cell morphology and maintaining cytoskeletal organization in a wide variety of cell types. Palladin has been shown previously to bind directly to three different actin-binding proteins vasodilator-stimulated phosphoprotein (VASP), alpha-actinin and ezrin, suggesting that it functions as an organizing unit that recruits actin-regulatory proteins to specific subcellular sites. Palladin contains sequences resembling a motif known to bind profilin. Here, we demonstrate that palladin is a binding partner for profilin, interacting with profilin via a poly proline-containing sequence in the amino-terminal half of palladin. Double-label immunofluorescence staining shows that palladin and profilin partially colocalize in actin-rich structures in cultured astrocytes. Our results suggest that palladin may play an important role in recruiting profilin to sites of actin dynamics. 相似文献
79.
Ccile Brocard Malika Es-Souni Leyla C Ramirez Norbert Latruffe Paulette Bournot 《Biology of the cell / under the auspices of the European Cell Biology Organization》1993,77(1):37-41
Summary— The response of two rat cell lines, Fao and MH1C1, and one human cell line, HepG2, to the peroxisome proliferator ciprofibrate, was studied. Using a fluorometric assay for palmitoyl-CoA oxidase, the dose- and time-dependent increase of this enzymatic activity was determined. From the lowest concentration (100 μM) stimulation is evident in the two rat cell lines. In the Fao line, the activity was stimulated reaching a seven-fold increase over the control level at 250 μM after 72 h of treatment. In the MH1C1 line, the maximum stimulation, four- to five-fold, was obtained at 250 and 500 μM after 72 h. In the HepG2 cell line, activity increased two-fold at 250 μM after 72 h reaching a three-fold increase at 1000 μM after 48 h. Ciprofibrate was more toxic to Fao cells than to MH1C1 and HepG2 cells which is also the order of the acyl-CoA oxidase stimulation by ciprofibrate. These preliminary results suggest that the two rat cell lines are appropriate for investigating the induction of peroxisomal β-oxidation enzymes and the expression of their genes. The HepG2 cell line is a complementary model for the study of interspecies differences in the response to peroxisomal proliferators and of the peroxisomal functions implied in the lipid metabolism of human liver. 相似文献
80.
Elhaïmeur F Nicod L Courderot-Masuyer C Robin S Guyon C Bouhaddi M Regnard J Richert L Berthelot A 《Biological trace element research》2005,107(3):263-276
Hypertension is known to be associated with an oxidative stress resulting from an imbalance of antioxidant defense mechanisms
in various tissues. The purpose of this study was to investigate the relationship between the increase of arterial blood pressure,
measured during the gradual development of experimental hypertension in deoxycorticosterone (DOCA)-salt-treated rats, and
an early imbalance of liver antioxidant status. The levels of liver oxidant/antioxidant markers and iron were studied during
the induction of hypertension in 3-, 6-, and 8-wk DOCA-salt-treated Sprague-Dawley rats. Hepatic antioxidant defenses were
decreased as early as 3 wk of hypertensive treatment: the decrease of peroxidase-reductase-transferase and catalase activities
was associated with a significant increase of thiobarbituric acid reactive substances (TBARS) levels. Liver oxidative stress
increased until 6 wk, and remained stable at 8 wk of DOCA-salt treatment. Concurrently, liver iron levels were increased at
6 wk and returned to normal values after 8 wk of hypertensive treatment. Iron seems to be an inductor of liver oxidative stress
and responsible for the persistent oxidative stress, most likely through secondary free-radical release. Thus, our data (1)
confirm that hypertension in DOCA-salt-treated rats might be a free-radical-dependent disease where hepatic oxidant/antioxidant
imbalance is obviously involved from the beginning of blood pressure elevation and (2) suggest that the use of suitable iron
chelators might reverse liver oxidative stress associated with the increase of blood pressure. 相似文献