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991.
Wissing J Godl K Brehmer D Blencke S Weber M Habenberger P Stein-Gerlach M Missio A Cotten M Müller S Daub H 《Molecular & cellular proteomics : MCP》2004,3(12):1181-1193
Small molecule inhibitors belonging to the pyrido[2,3-d]pyrimidine class of compounds were developed as antagonists of protein tyrosine kinases implicated in cancer progression. Derivatives from this compound class are effective against most of the imatinib mesylate-resistant BCR-ABL mutants isolated from advanced chronic myeloid leukemia patients. Here, we established an efficient proteomics method employing an immobilized pyrido[2,3-d]pyrimidine ligand as an affinity probe and identified more than 30 human protein kinases affected by this class of compounds. Remarkably, in vitro kinase assays revealed that the serine/threonine kinases Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK) and p38alpha were among the most potently inhibited kinase targets. Thus, pyrido[2,3-d]pyrimidines did not discriminate between tyrosine and serine/threonine kinases. Instead, we found that these inhibitors are quite selective for protein kinases possessing a conserved small amino acid residue such as threonine at a critical site of the ATP binding pocket. We further demonstrated inhibition of both p38 and RICK kinase activities in intact cells upon pyrido[2,3-d]pyrimidine inhibitor treatment. Moreover, the established functions of these two kinases as signal transducers of inflammatory responses could be correlated with a potent in vivo inhibition of cytokine production by a pyrido[2,3-d]pyrimidine compound. Thus, our data demonstrate the utility of proteomic methods employing immobilized kinase inhibitors for identifying new targets linked to previously unrecognized therapeutic applications. 相似文献
992.
Mps1 kinase plays an evolutionary conserved role in the mitotic spindle checkpoint. This system precludes anaphase onset until all chromosomes have successfully attached to spindle microtubules via their kinetochores. Mps1 overexpression in budding yeast is sufficient to trigger a mitotic arrest, which is dependent on the other mitotic checkpoint components, Bub1, Bub3, Mad1, Mad2, and Mad3. Therefore, Mps1 might act at the top of the mitotic checkpoint cascade. Moreover, in contrast to the other mitotic checkpoint components, Mps1 is essential for spindle pole body duplication in budding yeast. Centrosome duplication in mammalian cells might also be controlled by Mps1 , but the fission yeast homolog is not required for spindle pole body duplication. Our phenotypic characterizations of Mps1 mutant embryos in Drosophila do not reveal an involvement in centrosome duplication, while the mitotic spindle checkpoint is defective in these mutants. In addition, our analyses reveal novel functions. We demonstrate that Mps1 is also required for the arrest of cell cycle progression in response to hypoxia. Finally, we show that Mps1 and the mitotic spindle checkpoint are responsible for the developmental cell cycle arrest of the three haploid products of female meiosis that are not used as the female pronucleus. 相似文献
993.
Average protein density is a molecular-weight-dependent function 总被引:3,自引:0,他引:3
Fischer H Polikarpov I Craievich AF 《Protein science : a publication of the Protein Society》2004,13(10):2825-2828
The mass density of proteins is a relevant basic biophysical quantity. It is also a useful input parameter, for example, for three-dimensional structure determination by protein crystallography and studies of protein oligomers in solution by analytic ultracentrifugation. We have performed a critical analysis of published, theoretical, and experimental investigations about this issue and concluded that the average density of proteins is not a constant as often assumed. For proteins with a molecular weight below 20 kDa, the average density exhibits a positive deviation that increases for decreasing molecular weight. A simple molecular-weight-depending function is proposed that provides a more accurate estimate of the average protein density. 相似文献
994.
995.
Mazzatenta A Pelosi P Cellerino A 《Proceedings. Biological sciences / The Royal Society》2004,271(Z3):S46-S49
We have isolated a gene encoding for an olfactory sensory neuron (OSN)-specific protein in an invertebrate, the land snail Eobania vermiculata (GenBank accession number AY147909). Using in situ hybridization, we detected expression of its mRNA in the dendrite, cell body and axon of OSNs. By neural tracing, using the lipophilic tracer DiI and in situ hybridization, we have revealed the organization of OSNs and their connections with olfactory glomeruli in the land snail. Sequence and expression pattern analogy of land snail protein with olfactory marker protein (OMP) from vertebrates suggest that the land snail protein is an OMP-like protein. This protein could represent a plesiomorphic character in the evolution of olfactory proteins. 相似文献
996.
997.
Regulation of actin dynamics by WASP and WAVE family proteins 总被引:22,自引:0,他引:22
Stradal TE Rottner K Disanza A Confalonieri S Innocenti M Scita G 《Trends in cell biology》2004,14(6):303-311
998.
Sharon E Zündorf G Lévesque SA Beaudoin AR Reiser G Fischer B 《Bioorganic & medicinal chemistry》2004,12(23):6119-6135
Despite the significance of the elucidation of proteins' physicochemical parameters to understand various molecular phenomena, direct methods for measuring these parameters are not readily available. Here, we propose the use of 8-[p-amino-Ph]-epsilon-ATP, 3b, as a fluorescent probe for the elucidation of physicochemical parameters of binding sites in certain proteins. We synthesized novel fluorescent nucleotide analogues based on an extension of the epsilon-ATP scaffold. These analogues bear a primary or tertiary p-amino-phenyl moiety on the etheno-bridge. We explored the recognition of the fluorescent analogues by the target proteins: P2Y(1)-receptor (P2Y(1)-R) and NTPDase1. Based on the high affinity to the P2Y(1)-R (EC(50) 100nM), 3b proved a suitable probe for the investigation of this receptor. Next, we elucidated the dependencies of the absorption and emission spectra of 3b on environmental parameters, for establishing correlation equations. These equations will help determine the properties of the ATP-binding site from the spectral data of the protein-bound 3b. For this purpose, the sensitivity of the probe to acidity, dielectricity, H-bonding, viscosity, and to correlation between these parameters was determined. Thus, the pH-dependence of 3b emission intensity is bell shaped. At pH2.8 the quantum yield (phi) is enhanced 150-fold, as compared to neutral pH. The basic nitrogen atoms of 3b were assigned and pK(a) values were determined. A linear relationship was found between log phi and log viscosity, however, emission maxima (lambda(max)) remained constant. A linear relationship was found between both phi and lambda(max) and dielectricity, as measured in protic or aprotic solvents of comparable viscosity. pK(a)-like values were measured in acid-titrated alcohols with varying dielectricity but comparable viscosity, or with varying viscosity but comparable dielectricity. An inverse relationship and a linear relationship were found between the pK(a) values of 3b and the medium dielectricity and viscosity, respectively. These correlations help the calibration of properties of a protein ATP-binding site. 相似文献
999.
The geographical mosaic theory of coevolution predicts differences in the advance or trajectory of the coevolutionary process between local communities due to their composition and the strength of ecological selection pressures through competition and resource availability. In this study, we investigate local co-adaptation in different populations of a social parasite. We conducted cross-fostering experiments to test for interpopulational differences in raiding efficiency between various populations of a slave-making ant and the defence abilities of local hosts. Here, we demonstrate that the success of raids strongly depends on the combination of populations of the parasite Harpagoxenus sublaevis and its host Leptothorax acervorum, indicating very localized coevolution. We found no absolute differences between slave-maker populations; the outcome of an encounter depended more on whether the two opponents occur in sympatry or allopatry. Furthermore, this study supports the results of our earlier work, that the unparasitized English L. acervorum population is most aggressive against the parasite. 相似文献
1000.
Voynow JA Fischer BM Malarkey DE Burch LH Wong T Longphre M Ho SB Foster WM 《American journal of physiology. Lung cellular and molecular physiology》2004,287(6):L1293-L1302
Goblet cell hyperplasia in the superficial airway epithelia is a signature pathological feature of chronic bronchitis and cystic fibrosis. In these chronic inflammatory airway diseases, neutrophil elastase (NE) is found in high concentrations in the epithelial lining fluid. NE has been reported to trigger mucin secretion and increase mucin gene expression in vitro. We hypothesized that chronic NE exposure to murine airways in vivo would induce goblet cell metaplasia. Human NE (50 microg) or PBS saline was aspirated intratracheally by male Balb/c (6 wk of age) mice on days 1, 4, and 7. On days 8, 11, and 14, lung tissues for histology and bronchoalveolar lavage (BAL) samples for cell counts and cytokine levels were obtained. NE induced Muc5ac mRNA and protein expression and goblet cell metaplasia on days 8, 11, and 14. These cellular changes were the result of proteolytic activity, since the addition of an elastase inhibitor, methoxysuccinyl Ala-Ala-Pro-Val chloromethylketone (AAPV-CMK), blocked NE-induced Muc5ac expression and goblet cell metaplasia. NE significantly increased keratinocyte-derived chemokine and IL-5 in BAL and increased lung tissue inflammation and BAL leukocyte counts. The addition of AAPV-CMK reduced these measures of inflammation to control levels. These experiments suggest that NE proteolytic activity initiates an inflammatory process leading to goblet cell metaplasia. 相似文献