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991.
992.
Ligand-mediated activation of the cAMP-responsive guanine nucleotide exchange factor Epac 总被引:1,自引:0,他引:1
Rehmann H Schwede F Døskeland SO Wittinghofer A Bos JL 《The Journal of biological chemistry》2003,278(40):38548-38556
Epac is a cAMP-dependent exchange factor for the small GTP-binding protein Rap. The activity of Epac is inhibited by a direct interaction between the C-terminal helical part of the cAMP-binding domain, called the lid, and the catalytic region, which is released after binding of cAMP. Herein, we show that the activation properties are very sensitive to modifications of the cyclic nucleotide. Some analogues are inhibitory and others are stimulatory; some are characterized by a much higher activation potential than normal cAMP. Mutational analysis of Epac allows insights into a network of interactions between the cyclic nucleotides and Epac. Mutations in the lid region are able to amplify or to attenuate selectively the activation potency of cAMP analogues. The properties of cAMP analogues previously used for the activation of the cAMP responsive protein kinase A and of 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclicmonophosphate, an analogue highly selective for activation of Epac were investigated in detail. 相似文献
993.
994.
Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP binding cassette C2) 总被引:6,自引:0,他引:6
Zelcer N Huisman MT Reid G Wielinga P Breedveld P Kuil A Knipscheer P Schellens JH Schinkel AH Borst P 《The Journal of biological chemistry》2003,278(26):23538-23544
Multidrug resistance protein 2 (MRP2) belongs to the ATP binding cassette family of transporters. Its substrates include organic anions and anticancer drugs. We have used transport assays with vesicles derived from Sf9 insect cells overproducing MRP2 to study the interactions of drugs, organic anions, and bile acids with three MRP2 substrates: estradiol-17-beta-d-glucuronide (E217betaG), methotrexate, and glutathione-S-dinitrophenol. Complex inhibition and stimulation patterns were obtained, different from those observed with the related transporters MRP1 and MRP3. In contrast to a previous report, we found that the rate of E217betaG transport by MRP2 increases sigmoidally with substrate concentration indicative of homotropic cooperativity. Half-maximal transport was obtained at 120 microm E217betaG, in contrast to values < 20 microm for MRP1 and 3. MRP2 stimulators, such as indomethacin and sulfanitran, strongly increased the affinity of MRP2 for E217betaG (half-maximal transport rates at 65 and 16 microm E217betaG, respectively) and shifted the sigmoidal dependence of transport rate on substrate concentration to a more hyperbolic one, without substantially affecting the maximal transport rate. Sulfanitran also stimulated MRP2 activity in cells, i.e. the transport of saquinavir through monolayers of Madin-Darby canine kidney II cells. Some compounds that stimulate E217betaG transport, such as penicillin G or pantoprazole, are not detectably transported by MRP2, suggesting that they allosterically stimulate transport without being cotransported with E217betaG. We propose that MRP2 contains two similar but nonidentical ligand binding sites: one site from which substrate is transported and a second site that regulates the affinity of the transport site for the substrate. 相似文献
995.
This study analyses the social, physiological and motivational determinants of sexual activity for 644 married women in rural areas of Osun State, Nigeria. The data come from the Fertility Awareness and Pregnancy Avoidance study conducted in 1993-94. Sexual activity is measured by three continuous variables: weekly frequency of (1) total sexual activity, (2) coital-only sex and (3) both coital/non-coital sex. Analyses of variance were performed to test the difference in group means between the predictor variables and measures of sexual activity. Ordinary least squares regression analyses were then performed for the three dependent variables. Two models are used: the first contains only those variables associated with an individual's demographic, social and economic status, and the second adds predictor variables associated with motivational and physiological factors. Results show that while many socioeconomic variables by themselves are significantly associated with sexual activity measures, the addition of physiological and motivational variables weakens their effects and lessens their original statistical significance. Additionally, the socioeconomic and demographic factors associated with frequency of sexual activity are not necessarily the same ones significantly associated with coital-only or combined coital/non-coital sex. While other studies have tended to focus either on socioeconomic or physiological factors, the joint examination of both types of influences seems to indicate that the latter have more proximate effects on the frequency of both coital and non-coital sexual activity of married women in this population. Contraceptive protection is shown to be highly positively associated with all three of the sexual activity measures, empirically confirming the important relationship between contraception and both coital and non-coital forms of sexual activity. 相似文献
996.
Sebastian?Schuck Ana?Soloaga Gerhard?Schratt J?Simon?C?Arthur Alfred?NordheimEmail author 《BMC molecular biology》2003,4(1):6
Background
The regulation of the immediate-early gene c-fos serves as a paradigm for signal-activated gene induction. Lysophosphatidic acid is a potent serum-borne mitogen able to induce c-fos.Results
Analysing the signalling events following stimulation of mouse embryonic stem cells with serum and lysophosphatidic acid, we show that the extracellular signal-regulated kinase (ERK) pathway is involved in mediating c-fos induction. We demonstrate that the ERK-activated kinase MSK1 is required for full c-fos promoter activation, as well as for the phosphorylation of cAMP-responsive element (CRE) binding proteins. We propose that MSK1 contributes to ERK-mediated c-fos promoter activation by targeting CRE binding proteins.Conclusion
These results show that MSK1 is an important ERK-activated mediator of mitogen-stimulated c-fos induction. In addition, they indicate that MSK1 could act through CRE binding proteins to achieve c-fos promoter activation. Thus, they further our understanding of the complex regulation of the model immediate-early gene c-fos.997.
Petasites hybridus is used in Chinese herbal medicine. S-petasin is a bioactive compound isolated from leaves or roots of Petasites hybridus. S-petasin has been used to relieve gastrointestinal pain, lung disease, and spasms of the urogenital tract. However, the side effect of S-petasin on endocrine systems are still not clear. This study explored the effects of S-petasin on the release of corticosterone in vivo and in vitro. An intravenous injection of S-petasin (10 microg/kg) decreased both basal and adrenocorticotropin (ACTH)-induced plasma corticosterone concentration in male rats. In vitro, S-petasin (3 x 10(-6) - 10(-4) M) caused a significant reduction of basal and ACTH-stimulated release of corticosterone from the enzymatically dispersed rat zona fasciculata-reticularis (ZFR) cells in a dose-dependent manner. In order to study possible mechanisms, ZFR cells were incubated with S-petasin (10(-5) M) in the presence or absence of forskolin (adenylate cyclase activator, 10(-6) - 10(-4) M), 8-Br-cAMP (a cAMP analogue, 10(-6) 10(-4) M), 25-OH-cholesterol (pregnenolone biosynthesis precursor, 10(-5) M) combined with trilostane (a blocker of 3beta-hydroxysteriod dehydrogenase, 3beta-HSD, 10(-6) M) and deoxycorticosterone (corticosterone biosynthesis precursor, 10(-9) - 10(-6) M) at 37 degrees C for 1h. The concentration of pregnenolone and corticosterone in media were measured by radioimmunoassay. The stimulatory effects of corticosterone secretion induced by forskolin (10(-5) - 10(-4) M), 8-Br-cAMP (10(-5) - 10(-4) M) and deoxycorticosterone (10(-7) - 10(-6) M) were reduced by S-petasin at 10(-5) M. The stimulatory effects of pregnenolone secretion induced by 25-OH-cholesterol combined with or without trilostane was reduced by S-petasin at 10(-5) M. These results suggest that S-petasin inhibits the production of corticosterone from rat ZFR cells in part through decreasing the activities of adenylyl cyclase, P450scc and 11beta-hydroxylase. 相似文献
998.
Fritz JJ Lewin A Hauswirth W Agarwal A Grant M Shaw L 《Methods (San Diego, Calif.)》2002,28(2):276-285
Hammerhead ribozymes are catalytic RNAs that are being used to inhibit endogenous gene expression to study key components of basic biochemical pathways such as angiogenesis. In addition, these ribozymes have the potential to be used as components of gene therapy protocols for the treatment of disease states. We detail here a set of protocols for the design and testing of hammerhead ribozymes that will efficiently inhibit gene expression both in cell culture and in vivo. 相似文献
999.
Guertin KR Gardner CJ Klein SI Zulli AL Czekaj M Gong Y Spada AP Cheney DL Maignan S Guilloteau JP Brown KD Colussi DJ Chu V Heran CL Morgan SR Bentley RG Dunwiddie CT Leadley RJ Pauls HW 《Bioorganic & medicinal chemistry letters》2002,12(12):1671-1674
Further optimization of the beta-aminoester class of factor Xa (fXa) inhibitors is described culminating in the identification of 9c (FXV673), a potent and selective factor Xa inhibitor with excellent in vivo anticoagulant activity. An X-ray structure of FXV673 bound to human fXa is also presented. Based on its selectivity, potent in vivo activity and favorable pre-clinical safety profile, FXV673 was selected for further development and is currently undergoing clinical trials. 相似文献
1000.
We determined the complete nucleotide sequence of the 27.8-kb R-plasmid pTET3 from Corynebacterium glutamicum LP-6 which encodes streptomycin, spectinomycin, and tetracycline resistance. The antibiotic resistance determinant of pTET3 comprises an intI1-like gene, which was truncated by the insertion sequence IS6100, and the novel aminoglycoside adenyltransferase gene cassette aadA9. The deduced AADA9 protein showed 61% identity and 71% similarity to AADA6 of integron In51 from Pseudomonas aeruginosa. In addition, pTET3 carries the novel repressor-regulated tetracycline resistance determinant Tet 33 which revealed amino acid sequence homology to group 1 tetracycline efflux systems. The highest level of similarity was observed to the tetracycline efflux protein TetA(Z) from the C. glutamicum plasmid pAG1 with 65% identical and 77% similar amino acids. Each antibiotic resistance region of pTET3 is flanked by identical copies of the widespread insertion sequence IS6100 initially identified in Mycobacterium fortuitum. Transposition assays with a cloned copy of IS6100 revealed that this element is transpositionally active in C. glutamicum. These data suggest a central role of IS6100 in the evolutionary history of pTET3 by mediating the cointegrative assembly of resistance gene-carrying DNA segments. 相似文献