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101.
Chen B Dores MR Grimsey N Canto I Barker BL Trejo J 《The Journal of biological chemistry》2011,286(47):40760-40770
Signaling by protease-activated receptor-1 (PAR1), a G protein-coupled receptor (GPCR) for thrombin, is regulated by desensitization and internalization. PAR1 desensitization is mediated by β-arrestins, like most classic GPCRs. In contrast, internalization of PAR1 occurs through a clathrin- and dynamin-dependent pathway independent of β-arrestins. PAR1 displays two modes of internalization. Constitutive internalization of unactivated PAR1 is mediated by the clathrin adaptor protein complex-2 (AP-2), where the μ2-adaptin subunit binds directly to a tyrosine-based motif localized within the receptor C-tail domain. However, AP-2 depletion only partially inhibits agonist-induced internalization of PAR1, suggesting a function for other clathrin adaptors in this process. Here, we now report that AP-2 and epsin-1 are both critical mediators of agonist-stimulated PAR1 internalization. We show that ubiquitination of PAR1 and the ubiquitin-interacting motifs of epsin-1 are required for epsin-1-dependent internalization of activated PAR1. In addition, activation of PAR1 promotes epsin-1 de-ubiquitination, which may increase its endocytic adaptor activity to facilitate receptor internalization. AP-2 also regulates activated PAR1 internalization via recognition of distal C-tail phosphorylation sites rather than the canonical tyrosine-based motif. Thus, AP-2 and epsin-1 are both required to promote efficient internalization of activated PAR1 and recognize discrete receptor sorting signals. This study defines a new pathway for internalization of mammalian GPCRs. 相似文献
102.
Joana RF Abreu Wendy Dontje Sarah Krausz Daphne de Launay Paula B van Hennik Anne-Marieke van Stalborch Jean-Paul ten Klooster Marjolein E Sanders Kris A Reedquist Margriet J Vervoordeldonk Peter L Hordijk Paul P Tak 《Arthritis research & therapy》2010,12(1):1-14
Introduction
The Rho family GTPase Rac1 regulates cytoskeletal rearrangements crucial for the recruitment, extravasation and activation of leukocytes at sites of inflammation. Rac1 signaling also promotes the activation and survival of lymphocytes and osteoclasts. Therefore, we assessed the ability of a cell-permeable Rac1 carboxy-terminal inhibitory peptide to modulate disease in mice with collagen-induced arthritis (CIA).Methods
CIA was induced in DBA/1 mice, and in either early or chronic disease, mice were treated three times per week by intraperitoneal injection with control peptide or Rac1 inhibitory peptide. Effects on disease progression were assessed by measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. Serum levels of anti-collagen type II antibodies were measured by enzyme-linked immunosorbent assay. T-cell phenotypes and activation were assessed by fluorescence-activated cell sorting analysis. Results were analyzed using Mann-Whitney U and unpaired Student t tests.Results
Treatment of mice with Rac1 inhibitory peptide resulted in a decrease in paw swelling in early disease and to a lesser extent in more chronic arthritis. Of interest, while joint destruction was unaffected by Rac1 inhibitory peptide, anti-collagen type II antibody production was significantly diminished in treated mice, in both early and chronic arthritis. Ex vivo, Rac1 inhibitory peptide suppressed T-cell receptor/CD28-dependent production of tumor necrosis factor α, interferon γ and interleukin-17 by T cells from collagen-primed mice, and reduced induction of ICOS and CD154, T-cell costimulatory proteins important for B-cell help.Conclusions
The data suggest that targeting of Rac1 with the Rac1 carboxy-terminal inhibitory peptide may suppress T-cell activation and autoantibody production in autoimmune disease. Whether this could translate into clinically meaningful improvement remains to be shown. 相似文献103.
Blanco M Núñez L Tarrío N Canto E Becerra M González-Siso MI Cerdán ME 《FEMS yeast research》2007,7(5):702-714
Genome duplication, after the divergence of Saccharomyces cerevisiae from Kluyveromyces lactis along evolution, has been proposed as a mechanism of yeast evolution from strict aerobics, such as Candida albicans, to facultatives/fermentatives, such as S. cerevisiae. This feature, together with the preponderance of respiration and the use of the pentose phosphate pathway in glucose utilization, makes K. lactis a model yeast for studies related to carbon and oxygen metabolism. In this work, and based on the knowledge of the sequence of the genome of K. lactis, obtained by the Génolevures project, we have constructed DNA arrays from K. lactis including a limited amount of selected probes. They are related to the aerobiosis-hypoxia adaptation and to the oxidative stress response, and have been used to test changes in mRNA levels in response to hypoxia and oxidative stress generated by H(2)O(2). The study was carried out in both wild-type and rag2 mutant K. lactis strains in which glycolysis is blocked at the phosphoglucose isomerase step. This approach is the first analysis carried out in K. lactis for the majority of the genes selected. 相似文献
104.
BACKGROUND AND AIMS: Intra-specific variation in nectar chemistry under natural conditions has been only rarely explored, yet it is an essential aspect of our understanding of how pollinator-mediated selection might act on nectar traits. This paper examines intra-specific variation in nectar sugar composition in field and glasshouse plants of the bumblebee-pollinated perennial herbs Aquilegia vulgaris subsp. vulgaris and Aquilegia pyrenaica subsp. cazorlensis (Ranunculaceae). The aims of the study are to assess the generality of extreme intra-plant variation in nectar sugar composition recently reported for other species in the field, and gaining insight on the possible mechanisms involved. METHODS: The proportions of glucose, fructose and sucrose in single-nectary nectar samples collected from field and glasshouse plants were determined using high performance liquid chromatography. A hierarchical variance partition was used to dissect total variance into components due to variation among plants, flowers within plants, and nectaries within flowers. KEY RESULTS: Nectar of the two species was mostly sucrose-dominated, but composition varied widely in the field, ranging from sucrose-only to fructose-dominated. Most intra-specific variance was due to differences among nectaries of the same flower, and flowers of the same plant. The high intra-plant variation in sugar composition exhibited by field plants vanished in the glasshouse, where nectar composition emerged as a remarkably constant feature across plants, flowers and nectaries. CONCLUSIONS: In addition to corroborating the results of previous studies documenting extreme intra-plant variation in nectar sugar composition in the field, this study suggests that such variation may ultimately be caused by biotic factors operating on the nectar in the field but not in the glasshouse. Pollinator visitation and pollinator-borne yeasts are suggested as likely causal agents. 相似文献
105.
106.
107.
Identification of a locus on mouse chromosome 3 involved in differential susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease. 总被引:5,自引:3,他引:2 下载免费PDF全文
Theiler's virus-induced demyelinating disease results from a chronic infection in the white matter of the central nervous system and provides an excellent model for human multiple sclerosis. Like multiple sclerosis, there are genetic risk factors in disease development, including genes associated with the major histocompatibility complex and with those encoding the beta chain of the T-cell receptor. Comparisons of the susceptible DBA/2 and resistant C57BL/6 strains have indicated an important role for the H-2D locus and for a non-H-2 gene (not involving the beta chain of the T-cell receptor) in differential susceptibility. In the present report, analysis of recombinant-inbred strains (BXD) between the DBA/2 and C57BL/6 strains indicated that this non-H-2 locus is located at the centromeric end of chromosome 3 near (4 +/- 4 centimorgans) the carbonic anhydrase-2 (Car-2) enzyme locus. 相似文献
108.
109.
Chromosomal DNA from 23 closely related, pathogenic strains of Escherichia
coli was digested and probed for the insertion sequences IS1, IS2, IS4,
IS5, and IS30. Under the assumption that elements residing in DNA
restriction fragments of the same apparent length are identical by descent,
parsimony analysis of these characters yielded a unique phylogenetic tree.
This analysis not only distinguished among bacterial strains that were
otherwise identical in their biochemical characteristics and enzyme
electrophoretic mobilities, but certain aspects of the topology of the tree
were consistent across several unrelated insertion elements. The
distribution of IS elements was then reexamined in light of the inferred
phylogenetic relationships to investigate the biological properties of the
elements, such as rates of insertion and deletion, and to discover apparent
recombinational events. The analysis shows that the pattern of distribution
of insertion elements in the bacterial genome is sufficiently stable for
epidemiological studies. Although the rate of recombination by conjugation
has been postulated to be low, at least two such events appear to have
taken place.
相似文献
110.
Russowsky D Canto RF Sanches SA D'Oca MG de Fátima A Pilli RA Kohn LK Antônio MA de Carvalho JE 《Bioorganic chemistry》2006,34(4):173-182
The synthesis and differential antiproliferative activity of monastrol (1a), oxo-monastrol (1b) and eight oxygenated derivatives 3a,b-6a,b on seven human cancer cell lines are described. For all evaluated cell lines, monastrol (1a) was shown to be more active than its oxo-analogue, except for HT-29 cell line, suggesting the importance of the sulfur atom for the antiproliferative activity. Monastrol (1a) and the thio-derivatives 3a, 4a and 6a displayed relevant antiproliferative properties with 3,4-methylenedioxy derivative 6a being approximately more than 30 times more potent than monastrol (1a) against colon cancer (HT-29) cell line. 相似文献