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排序方式: 共有374条查询结果,搜索用时 15 毫秒
31.
Shao H Xu X Mastrangelo MA Jing N Cook RG Legge GB Tweardy DJ 《The Journal of biological chemistry》2004,279(18):18967-18973
Stat3 is an Src homology (SH)2-containing protein constitutively activated in a wide variety of human cancers following its recruitment to YXXQ-containing motifs, which results in resistance to apoptosis. Despite resolution of the crystal structure of Stat3 homodimer bound to DNA, the structural basis for the unique specificity of Stat3 SH2 for YXXQ-containing phosphopeptides remains unresolved. We tested three models of this interaction based on computational analysis of available structures and sequence alignments, two of which assumed an extended peptide configuration and one in which the peptide had a beta-turn. By using peptide immunoblot affinity assays and mirror resonance affinity analysis, we demonstrated that only phosphotyrosine (Tyr(P)) peptides containing +3 Gln (not Leu, Met, Glu, or Arg) bound to wild type Stat3. Examination of a series of wild type and mutant Stat3 proteins demonstrated loss of binding to pYXXQ-containing peptides only in Stat3 mutated at Lys-591 or Arg-609, whose side chains interact with the Tyr(P) residue, and Stat3 mutated at Glu-638, whose amide hydrogen bonds with oxygen within the +3 Gln side chain when the peptide ligand assumes a beta-turn. These findings support a model for Stat3 SH2 interactions that could form the basis for anticancer drugs that specifically target Stat3. 相似文献
32.
Cullin 4 (Cul4), a member of the evolutionally conserved cullin protein family, serves as a scaffold to assemble multisubunit ubiquitin E3 ligase complexes. Cul4 interacts with the Ring finger-containing protein ROC1 through its C-terminal cullin domain and with substrate recruiting subunit(s) through its N-terminus. Previous studies have demonstrated that Cul4 E3 ligase ubiquitylates key regulators in cell cycle control and mediates their degradation through the proteasomal pathway, thus contributing to genome stability. Recent studies from several groups have revealed that Cul4 E3 ligase can target histones for ubiquitylation, and importantly, ubiquitylation of histones may facilitate the cellular response to DNA damage. Therefore, histone ubiquitylation by Cul4 E3 ligase constitutes a novel mechanism through which Cul4 regulates chromatin function and maintains genomic integrity. We outline these studies and suggest that histone ubiquitylation might play important roles in Cul4-regualted chromatin function including the cellular response to DNA damage and heterochromatin gene silencing. 相似文献
33.
Yvet E Noordman Patrick AM Jansen Wiljan JAJ Hendriks 《Journal of molecular signaling》2006,1(1):1-11
Background
Spatio-temporal control of extracellular signal-regulated kinase (ERK) activity, a critical determinant of the cell's response to growth factors, requires timely dephosphorylation of its regulatory tyrosine and/or threonine residue by MAPK phosphatases. We studied the physiological role of kinase interaction motif (KIM)-containing protein tyrosine phosphatases (PTPs) in the control of EGF- and NGF-induced ERK activity in neuroendocrine PC12 cells.Results
We found a single KIM-containing PTP to be endogenously expressed in rat PC12 cells: the transmembrane PTPRR isoform termed PCPTP1. Protein knock-down of PCPTP1, or fourfold overexpression of its mouse orthologue, PTPBR7, left EGF- and NGF-induced ERK1/2 activity in PC12 cells unaltered. Ectopic expression of cytosolic PTPRR isoforms, however, resulted in reduced EGF-induced ERK1/2 activity, an effect that was dependent on the phosphatase activity and the KIM-domain of these PTPs.Conclusion
The finding that robust changes in tyrosine-specific MAPK phosphatase expression levels have minor effects on temporal ERK1/2 activity control in PC12 cells suggests that dual-specificity MAPK phosphatases may act as major regulators of growth factor-induced ERK1/2 signaling in these cells. 相似文献34.
Albart Coster John WM Bastiaansen Mario PL Calus Johan AM van Arendonk Henk Bovenhuis 《遗传、选种与进化》2010,42(1):9
The objective of this simulation study was to compare the effect of the number of QTL and distribution of QTL variance on the accuracy of breeding values estimated with genomewide markers (MEBV). Three distinct methods were used to calculate MEBV: a Bayesian Method (BM), Least Angle Regression (LARS) and Partial Least Square Regression (PLSR). The accuracy of MEBV calculated with BM and LARS decreased when the number of simulated QTL increased. The accuracy decreased more when QTL had different variance values than when all QTL had an equal variance. The accuracy of MEBV calculated with PLSR was affected neither by the number of QTL nor by the distribution of QTL variance. Additional simulations and analyses showed that these conclusions were not affected by the number of individuals in the training population, by the number of markers and by the heritability of the trait. Results of this study show that the effect of the number of QTL and distribution of QTL variance on the accuracy of MEBV depends on the method that is used to calculate MEBV. 相似文献
35.
36.
Terai M Eto M Young GD Berd D Mastrangelo MJ Tamura Y Harigaya K Sato T 《Cancer immunology, immunotherapy : CII》2012,61(2):145-155
We previously reported that substantial amounts of IL-10, an immunomodulatory cytokine, are produced by cell suspensions of
fresh human metastatic melanoma tissues. Production diminished with continuous culturing of cells, which suggests a pivotal
interactive role between melanoma cells and the tumor microenvironment. In this study, we found that the culture media obtained
from LPS-stimulated peripheral blood mononuclear cells induced IL-10 production by metastatic melanoma cells. Of the multiple
cytokines present in the conditioned culture media, IL-6 was identified as the inducer of IL-10 production. A neutralizing
antibody against IL-6 completely blocked the conditioned medium-induced IL-10 production. Metastatic melanoma cells that constitutively
produce low amount of IL-10 increased IL-10 production in response to recombinant human IL-6 in a dose-dependent fashion.
The response to exogenously added IL-6 was less significant in melanoma cells that produced high amounts of IL-6, probably
due to pre-existing autocrine stimulation of IL-10 by endogenous IL-6. On the other hand, metastatic melanoma cells that do
not constitutively produce IL-10 protein did not respond to exogenous IL-6. In IL-6-responsive melanoma cells, IL-6 increased
STAT3 phosphorylation and inhibition of STAT3 signaling using siRNA or inhibitors for JAKs diminished IL-6-induced IL-10 production.
In addition, inhibition of MEK and PI3K, but not mTOR, interfered with IL-10 production. Taken together, the data suggest
that blocking of these signals leading to IL-10 production is a potential strategy to enhance an anti-melanoma immune response
in metastatic melanoma. 相似文献
37.
Mastrangelo E Bolognesi M Milani M 《Biochemical and biophysical research communications》2012,417(1):84-87
Motor proteins are involved in crucial cell activities, such as cargo transport or nucleic acid remodeling, by converting the free energy of ATP hydrolysis into motion or mechanical work. Flavivirus helicase is a motor protein involved in dsRNA separation during viral replication, thus essential for virus infection. Since a clear vision of the protein activity, in particular of the relationship between ATP cycling and dynamics, is missing, we carried over a molecular dynamics study on Dengue virus helicase in its ATP bound and unbound states. Our simulations show different opening levels of the ssRNA access site to the helicase core. Specifically, we show that ATP induces a closed state into the ssRNA access site, likely involved in the helicase unwinding activity. 相似文献
38.
The aim of this work was to sequence the promoter region of β-lactoglobulin (BLG) gene in four sheep breeds, in order to identify polymorphisms, infer and analyze haplotypes, and phylogenetic relationship
among the Valle del Belice breed and the other three breeds considered as ancestors. Sequencing analysis and alignment of
the obtained sequences showed the presence of 36 single nucleotide polymorphisms (SNPs) and one deletion. A total of 22 haplotypes
found in “best” reconstruction were inferred considering the 37 polymorphic sites identified. Haplotypes were used for the
reconstruction of a phylogenetic tree using the Neighbor-Joining algorithm. The number of polymorphisms identified showed
high variability within breeds. Analysis of genetic diversity indexes showed that the Sarda breed presented the lowest nucleotide
diversity, whereas the Comisana breed presented the highest one. Comparing the nucleotide diversity among breeds, the highest
value was obtained between Valle del Belice and Pinzirita breeds, whereas the lowest one was between Valle del Belice and
Sarda breeds. Considering that polymorphisms in the promoter region of BLG gene could have a functional role associated with milk composition, the lowest value of nucleotide diversity between Valle
del Belice and Sarda breeds may be related to a higher similarity of milk composition of these two breeds compared to the
others. Further analyses will be conducted in order to evaluate the possible correlation between the genetic diversity indexes
and the BLG content in milk of our breeds. 相似文献
39.
Genetic diversity studies in domestic animals aim at evaluating genetic variation within and across breeds mainly for conservation purposes. In Sicily, dairy sheep production represents an important resource for hilly and mountain areas economy. Their milk is used for the production of traditional raw milk cheeses, sometimes protected designation of origin (PDO) cheeses. In some cases, the quality of these products is linked to a specific breed, i.e. mono-breed labelled cheeses and it is therefore important to be able to distinguish the milk of a breed from that of others, in order to guarantee both the consumer and the breed itself. In order to investigate the genetic structure and to perform an assignment test, a total of 331 individuals (Barbaresca, BAR n = 57, Comisana, COM n = 65, Pinzirita, PIN n = 75, Sarda, SAR n = 64, and Valle del Belice, VDB n = 70) were analysed using a panel of 20 microsatellite markers. A total of 259 alleles were observed with average polymorphic information content equal to 0.76, showing that the microsatellites panel used was highly informative. Estimates of observed heterozygosity ranged from 0.65 in the BAR breed to 0.75 in the COM breed. The low value of genetic differentiation among breeds (Fst = 0.049) may indicate that these breeds are little differentiated probably due to common history and breeding practices. The low Fis and Fit values indicated low level of inbreeding within and among breeds. The unrooted neighbor-joining dendrogram obtained from the Reynold's genetic distances, and factorial correspondence analysis revealed a separation between BAR and the other sheep breeds. Recent migration rates were estimated, showing that four out of the five breeds have not received a significant proportion of migrants. Only for the PIN breed a recent introgression rate from the VDB breed (7.2%) was observed. The Bayesian assignment test showed that BAR and SAR breeds had a more definite genetic structure (proportion of assignment of 92% and 86.6%, respectively), whereas the lowest assignment value was found in the PIN breed (67.1%). Our results indicated high genetic variability, low inbreeding and low genetic differentiation, except for BAR breed, and were in accordance with geographical location, history, and breeding practices. The low robustness of the assignment test makes it unfeasible for traceability purposes, due to the high level of admixture, in particular for COM, PIN and VDB. 相似文献
40.
Bianchi A Ugazzi M Ferrante L Lecis D Scavullo C Mastrangelo E Seneci P 《Bioorganic & medicinal chemistry letters》2012,22(6):2204-2208
A set of phenyl-substituted Smac mimetics/IAP inhibitor analogues of lead compound 2a was synthesized, aiming to retain its strong cell-free potency while increasing its bioavailability. Seventeen compounds 2b-r were prepared and characterized in vitro, using cell-free and cellular assays. Among them, the p-CF(3) substituted analogue 2m showed the best permeability through cell membranes, and was selected for further in vitro and in vivo studies due to its strong, sub-micromolar cellular potency. 相似文献