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At least 613 records · Page 34Linked to original sources
PubMed2002

Restoration of silencing in Saccharomyces cerevisiae by tethering of a novel Sir2-interacting protein, Esc8.

We previously described two classes of SIR2 mutations specifically defective in either telomeric/HM silencing (class I) or rDNA silencing (class II) in S. cerevisiae. Here we report the identification of genes whose protein products, when either overexpressed or directly tethered to the locus in question, can establish silencing in SIR2 class I mutants. Elevated dosage of SCS2, previously implicated as a regulator of both inositol biosynthesis and telomeric silencing, suppressed the dominant-negative effect of a SIR2-143 mutation. In a genetic screen for proteins that restore silencing when tethered to a telomere, we isolated ESC2 and an uncharacterized gene, (YOL017w), which we call ESC8. Both Esc2p and Esc8p interact with Sir2p in two-hybrid assays, and the Esc8p-Sir2 interaction is detected in vitro. Interestingly, Esc8p has a single close homolog in yeast, the ISW1-complex factor Ioc3p, and has also been copurified with Isw1p, raising the possibility that Esc8p is a component of an Isw1p-containing nucleosome remodeling complex. Whereas esc2 and esc8 deletion mutants alone have only marginal silencing defects, cells lacking Isw1p show a strong silencing defect at HMR but not at telomeres. Finally, we show that Esc8p interacts with the Gal11 protein, a component of the RNA pol II mediator complex.

Adenosine Triphosphatases↗
PubMed1986

Allergic diseases in the lungs.

Four basic immune reactions in the lung are fundamental to our understanding of allergic lung diseases. The first, immediate hypersensitivity, principally involves airway obstruction because of hypersecretion and bronchospasm. Resulting roentgenographic changes are those of large and small airway disease. The second reaction, cytotoxic antibody-mediated disease, produces air space filling by hemorrhage. The third form, immune complex-mediated hypersensitivity, causes mixed patchy consolidation and interstitial roentgenographic patterns caused by inflammation stimulated by antigen-antibody complexes. Fourth, cell-mediated immunity usually produces a granulomatous reaction, roentgenographically manifest by nodules, masses, and enlarged lymph nodes. Applying our understanding of these four basic reactions permits understanding the common allergic disease of the lungs: hypersensitivity pneumonitis, asthma, allergic bronchopulmonary fungal disease, chronic eosinophilic pneumonia, hypereosinophilic syndrome, Goodpasture's syndrome and idiopathic pulmonary hemosiderosis (IPH), Wegener's granulomatosis, and allergic granulomatosis (Churg-Strauss disease). The clinical, pathologic, and roentgenographic manifestations of these diseases are explained and related to the basic immune mechanisms.

Alveolitis, Extrinsic Allergic↗
PubMed2001

The Ras/PKA signaling pathway of Saccharomyces cerevisiae exhibits a functional interaction with the Sin4p complex of the RNA polymerase II holoenzyme.

Saccharomyces cerevisiae cells enter into the G(0)-like resting state, stationary phase, in response to specific types of nutrient limitation. We have initiated a genetic analysis of this resting state and have identified a collection of rye mutants that exhibit a defective transcriptional response to nutrient deprivation. These transcriptional defects appear to disrupt the control of normal growth because the rye mutants are unable to enter into a normal stationary phase upon nutrient deprivation. In this study, we examined the mutants in the rye1 complementation group and found that rye1 mutants were also defective for stationary phase entry. Interestingly, the RYE1 gene was found to be identical to SIN4, a gene that encodes a component of the yeast Mediator complex within the RNA polymerase II holoenzyme. Moreover, mutations that affected proteins within the Sin4p module of the Mediator exhibited specific genetic interactions with the Ras protein signaling pathway. For example, mutations that elevated the levels of Ras signaling, like RAS2(val19), were synthetic lethal with sin4. In all, our data suggest that specific proteins within the RNA polymerase II holoenzyme might be targets of signal transduction pathways that are responsible for coordinating gene expression with cell growth.

Cell Division↗
PubMed2004

Vitamin D-interacting protein 205 (DRIP205) coactivation of estrogen receptor alpha (ERalpha) involves multiple domains of both proteins.

Vitamin D-interacting protein 205 (DRIP205) is a mediator complex protein that anchors the complex to the estrogen receptor (ER) and other nuclear receptors (NRs). In ZR-75 breast cancer cells treated with 17beta-estradiol (E2) and transfected with a construct containing three tandem estrogen responsive elements (pERE(3)), DRIP205 coactivates ERalpha-mediated transactivation. DRIP205Delta587-636 is a DRIP205 mutant in which both NR boxes within amino acids 587-636 have been deleted and, in parallel transfection studies, DRIP205Delta587-636 also coactivates ERalpha. Moreover, both wild-type and variant DRIP205 also colocalize with ERalpha in the nuclei of transfected cells. Extensive deletion analysis of DRIP205 shows that multiple domains of this protein play a role in coactivation of ERalpha and in interactions with ERalpha. Coactivation of ERalpha by DRIP205 does not require NR boxes, and variants with deletion of N-terminal (amino acids 1-639) and C-terminal (amino acids 576-1566) significantly coactivate ERalpha. DRIP205 resembles p160 coactivators that also interact with multiple regions of ERalpha; however, unlike p160 coactivators, DRIP205 coactivation of ERalpha does not require NR boxes.

Animals↗
PubMed2001

Gell and Coombs's classification: is it still valid?

The Gell and Coombs's classification divides drug allergies into four pathophysiological types, namely anaphylaxis (type I), antibody-mediated cytotoxic reactions (type II), immune complex-mediated reactions (type III), and delayed type hypersensitivity (type IV). Although this classification was proposed more than 30 years ago, it is still widely used. As only a limited number of drug allergies fit into this classification which does not include our current understanding of the immune response, its use is not recommended, particularly in the context of the preclinical safety evaluation of new therapeutic agents. In fact, three different situations can be identified, namely pseudo-allergic reactions, primarily antibody-mediated reactions and cell-mediated reactions, which could serve as a basis for modern and more adequate classifications

Anaphylaxis↗
PubMed1996

[Cell adhesion molecules on platelet].

Platelets are anucleated blood cells that play a fundamental role in the initiation of hemostasis. In addition to platelet adhesion to the extracellular matrix, aggregation or platelet-platelet interaction is a requisite event in hemostasis. Some glycoproteins on platelet membranes mediate adhesion platelets. The glycoprotein (GP) Ib/IX/V complex is important in platelet adhesion and the GPIIb/IIIa complex mediate platelet to platelet interaction. P-selectin is a member of the selectin family and is transferred from secretory granules to the surface of activated platelets. P-selectin may function to mediate the interaction between activated platelets and leucocytes. We reviewed structure, function, biological roles and clinical application of three platelet-associated adhesion molecules.

Animals↗
PubMed2002

External control of Her2 expression and cancer cell growth by targeting a Ras-linked coactivator.

Overproduction of the Her2 oncoprotein has been found in approximately 30% of breast tumors, and patients who have Her2 excesses typically have more aggressive disease. Here we show that the expression of the Her2 gene can be decreased by inhibiting the interaction of the two cancer-linked proteins, DRIP130/CRSP130/Sur-2 (a Ras-linked subunit of human mediator complexes) and ESX (an epithelial-restricted transcription factor). Disruption of the interaction by a short cell-permeable peptide reduced the expression of the Her2 gene and specifically impaired the growth and viability of Her2-overexpressing breast cancer cells. The association of ESX with DRIP130 is mediated by a small hydrophobic face of an 8-aa helix in ESX, suggesting a therapeutic approach to incapacitating the Her2 gene by small organic molecules.

Amino Acid Sequence↗
PubMed1992

Canine distemper virus-immune complexes induce bystander degeneration of oligodendrocytes.

Demyelination in chronic canine distemper encephalitis may be the result of a bystander effect in which the antiviral immune response is involved. In the present report we demonstrate that canine distemper virus-antiviral antibody immune complexes induce oligodendroglial degeneration in mixed brain cell cultures, particularly at the level of the cell processes. The involvement of macrophages as effector cells in this process was confirmed by depletion of these cells from the cultures which prevented the immune complex-mediated oligodendroglial degeneration. Canine distemper virus-immune complex-induced oligodendroglial pathology is thought to be mediated by toxic factors released from stimulated macrophages, this bystander effect demonstrated here in vitro may be relevant to the mechanisms of demyelination in vivo, in which virus persistence plays an important role.

Animals↗
PubMed2005

The recessive epigenetic swellmap mutation affects the expression of two step II splicing factors required for the transcription of the cell proliferation gene STRUWWELPETER and for the timing of cell cycle arrest in the Arabidopsis leaf.

Generally, cell division can be uncoupled from multicellular development, but more recent evidence suggests that cell cycle progression and arrest is coupled to organogenesis and growth. We describe a recessive mutant, swellmap (smp), with reduced organ size and cell number. This defect is partially compensated for by an increase in final cell size. The mutation causes a precocious arrest of cell proliferation in the organ primordium and possibly reduces the rate of cell division there. The mutation proved to be an epigenetic mutation (renamed smp(epi)) that defined a single locus, SMP1, but affected the expression of both SMP1 and a second very similar gene, SMP2. Both genes encode CCHC zinc finger proteins with similarities to step II splicing factors involved in 3' splice site selection. Genetic knockouts demonstrate that the genes are functionally redundant and essential. SMP1 expression is associated with regions of cell proliferation. Overexpression of SMP1 produced an increase in organ cell number and a partial decrease in cell expansion. The smp(epi) mutation does not affect expression of eukaryotic cell cycle regulator genes CYCD3;1 and CDC2A but affects expression of the cell proliferation gene STRUWWELPETER (SWP) whose protein has similarities to Med150/Rgr1-like subunits of the Mediator complex required for transcriptional activation. Introduction of SWP cDNA into smp(epi) plants fully restored them to wild-type, but the expression of both SMP1 and SMP2 were also restored in these lines, suggesting a physical interaction among the three proteins and/or genes. We propose that step II splicing factors and a transcriptional Mediator-like complex are involved in the timing of cell cycle arrest during leaf development.

Amino Acid Sequence↗
PubMed2003

How is complex second-order motion processed?

Converging psychophysical and electrophysiological evidence suggests that first-order (luminance-defined) complex motion types i.e., radial and rotational motion, are processed by specialized extrastriate motion mechanisms. We ask whether radial and rotational second-order (texture-defined) motion patterns are processed in a similar manner. The motion sensitivity to translating, radiating and rotating motion patterns of both first-order (luminance-modulated noise) and second-order (contrast-modulated noise) were measured for patterns presented at four different exposure durations (106, 240, 500 and 750 ms). No significant difference in motion sensitivity was found across motion type for the first-order motion class across exposure duration (i.e., from 240 to 750 ms) whereas direction-identification thresholds for radiating and rotating second-order motion were significantly greater than that of the second-order translational stimuli. Furthermore, thresholds to all second-order motion stimuli increased at a significantly faster rate with decreasing exposure duration compared to those of first-order motion. Interestingly, simple and complex second-order thresholds increased at similar rates. Taken together, the results suggest that complex second-order motion is not analyzed in a sequential manner. Rather, it seems that the same 'hard-wired' mechanisms responsible for complex first-order motion processing also mediate complex second-order motion, but not before the pre-processing (i.e., rectification) of local second-order motion signals.

Adult↗
PubMed1998

Crystal structure of 180 degree K of bis-3, 5-diisopropylsalicylatobisdimethylsulfoxidozinc(II) and the inhibition of seizures and polymorphonuclear leukocyte chemiluminescence.

Dimethylsulfoxide (DMSO) formed a ternary complex when mixed with a Zn-3, 5-diisopropylsalicylate complex of unknown structure. The structure of this new ternary complex was characterized in an initial effort to understand the nature of this compound. Since the original complex is known to have anticonvulsant activity, the new ternary complex was also examined for anticonvulsant activity. The original complex was examined for inhibition of the polymorphonuclear leukocyte (PMNL) respiratory burst in an effort to mechanistically account for zinc complex mediated anticonvulsant activity. Dissolving the structurally unknown complex in DMSO gave crystals of a characterizable complex with an empirical formula C30H46O8S2Zn. Crystallographic data: P 1, Z = 2, a = 8.06(1), b = 12.452(2), c = 17.951(2) A, alpha = 74.42(l), beta = 77.07(1), gamma = 89.50(1) degree. The structure was refined to R = 0.03, RW = 0.04 for 3815 independent reflections with I > 2 sigma(I). This complex is mononuclear, with two 3,5-diisopropylsalicylate ligands and two bonded DMSO ligands, Zn(II)(3,5-DIPS)2(DMSO)2, Zn(II) is coordinate covalently bonded to four O atoms in a strongly distorted tetrahedral arrangement. Each DMSO ligates via its sulfoxide O atom while each 3,5-diisopropylsalicylate ligand is monodentate The non-ligating carbonyl O atom of each 3,5-DIPS is free except for an intramolecular hydrogen bond from the hydroxy group of the same ligand. Both 3,5-DIPS acid and Zn(II)(3,5-DIPS)2(DMSO)2 were examined for anticonvulsant activity in the Maximal Electroshock (MES) and Metrazol (MET) models of seizures and found to prevent both types of seizures. The Zn complex was qualitatively and quantitatively more effective than treatment with the free ligand. The influence of a Zn 3,5-DIPS complex and of the ligand 3,5-DIPS on PMNL oxidative metabolism was also studied to help understand the mechanism of anticonvulsant activity of these compounds. A dose-related and significant decrease in chemiluminescent (CL) response to opsonized Zymosan was observed, and the Zn complex was significantly more effective than the free ligand. It is concluded that mononuclear Zn complexes have anticonvulsant activity in Grand Mal and Petit Mal models of seizure possibly due to inhibition of the synthesis of superoxide or down-regulation of Nitric Oxide Synthase in activated phagocytic cells of the central nervous system.

Animals↗
PubMed2006

Smc5/6 is required for repair at collapsed replication forks.

In eukaryotes, three pairs of structural-maintenance-of-chromosome (SMC) proteins are found in conserved multisubunit protein complexes required for chromosomal organization. Cohesin, the Smc1/3 complex, mediates sister chromatid cohesion while two condensin complexes containing Smc2/4 facilitate chromosome condensation. Smc5/6 scaffolds an essential complex required for homologous recombination repair. We have examined the response of smc6 mutants to the inhibition of DNA replication. We define homologous recombination-dependent and -independent functions for Smc6 during replication inhibition and provide evidence for a Rad60-independent function within S phase, in addition to a Rad60-dependent function following S phase. Both genetic and physical data show that when forks collapse (i.e., are not stabilized by the Cds1Chk2 checkpoint), Smc6 is required for the effective repair of resulting lesions but not for the recruitment of recombination proteins. We further demonstrate that when the Rad60-dependent, post-S-phase Smc6 function is compromised, the resulting recombination-dependent DNA intermediates that accumulate following release from replication arrest are not recognized by the G2/M checkpoint.

Cell Cycle↗
PubMed2002

Binding of the RING polycomb proteins to specific target genes in complex with the grainyhead-like family of developmental transcription factors.

The Polycomb group (PcG) of proteins represses homeotic gene expression through the assembly of multiprotein complexes on key regulatory elements. The mechanisms mediating complex assembly have remained enigmatic since most PcG proteins fail to bind DNA. We now demonstrate that the human PcG protein dinG interacts with CP2, a mammalian member of the grainyhead-like family of transcription factors, in vitro and in vivo. The functional consequence of this interaction is repression of CP2-dependent transcription. The CP2-dinG interaction is conserved in evolution with the Drosophila factor grainyhead binding to dring, the fly homologue of dinG. Electrophoretic mobility shift assays demonstrate that the grh-dring complex forms on regulatory elements of genes whose expression is repressed by grh but not on elements where grh plays an activator role. These observations reveal a novel mechanism by which PcG proteins may be anchored to specific regulatory elements in developmental genes.

Amino Acid Motifs↗
PubMed1986

Antiphlogistic effect of catalase on experimental phacoanaphylactic endophthalmitis.

Oxygen-derived free radicals generated by polymorphonuclear leukocytes have recently been implicated as important pathogenic mediators of tissue damage in immune complex-mediated acute inflammatory reactions. In order to study the role of oxygen radicals in experimentally induced phacoanaphylactic endophthalmitis, rats were immunized with soluble bovine lens protein and, following surgical disruption of the anterior lens capsule, subjected to treatment with catalase. Our data show that phacoanaphylactic endophthalmitis, as determined morphologically and by measurements of retinal edema, choroidal inflammation, retinal hemorrhage and necrotizing vasculitis, is greatly diminished in catalase-treated animals. This protective effect of catalase indicates that hydrogen peroxide (H2O2) and/or conversion products of H2O2 (e.g., hydroxyl radical, hypochlorous acid) may play an important role in the development of experimental phacoanaphylactic endophthalmitis.

Animals↗
PubMed2003

The Drosophila trithorax group gene tonalli (tna) interacts genetically with the Brahma remodeling complex and encodes an SP-RING finger protein.

The trithorax group genes are required for positive regulation of homeotic gene function. The trithorax group gene brahma encodes a SWI2/SNF2 family ATPase that is a catalytic subunit of the Brm chromatin-remodeling complex. We identified the tonalli (tna) gene in Drosophila by genetic interactions with brahma. tna mutations suppress Polycomb phenotypes and tna is required for the proper expressions of the Antennapedia, Ultrabithorax and Sex combs reduced homeotic genes. The tna gene encodes at least two proteins, a large isoform (TnaA) and a short isoform (TnaB). The TnaA protein has an SP-RING Zn finger, conserved in proteins from organisms ranging from yeast to human and thought to be involved in the sumoylation of protein substrates. Besides the SP-RING finger, the TnaA protein also has extended homology with other eukaryotic proteins, including human proteins. We show that tna mutations also interact with mutations in additional subunits of the Brm complex, with mutations in subunits of the Mediator complex, and with mutations of the SWI2/SNF2 family ATPase gene kismet. We propose that Tna is involved in postranslational modification of transcription complexes.

Amino Acid Sequence↗
PubMed2006

Games researchers play--extreme-groups analysis and mediation analysis in longitudinal occupational health research.

OBJECTIVES: The study of causal processes using a longitudinal design is often hampered by two methodological problems. First, the lagged effects of a predictor variable on an outcome variable tend to be weak after control for a previous measure of this outcome. One approach that is advocated when effects are weak is to increase the extremeness of the study groups; this step often increases the significance and sizes of effects. Second, causal links are often mediated through third variables, and thus relatively complex mediational analyses are needed to understand the causal processes underlying particular associations. The present paper shows whether and when these two approaches are useful in longitudinal research. METHODS: The two approaches were evaluated using data from a three-wave study among 1251 newcomers from various Western countries (mean age 20.6 years, 59% female). RESULTS: Although the significances and effect sizes indeed increased with increasing extremeness of the study groups, extreme-groups analysis in the context of a longitudinal design may grossly bias findings. Cross-sectional applications of mediation analysis cannot provide evidence for any mediational model. Longitudinal models are better suited for examining mediation. CONCLUSIONS: Rather than using extreme-groups analysis to obtain significant effects across time, researchers should maximize the amount of change in their data by focusing on groups for which change can be expected. Especially multiphase longitudinal data sets offer good opportunities for analyzing mediation models.

Adult↗
PubMed1979

Direct Coombs antiglobulin reactions in Gambian children with Plasmodium falciparum malaria. I. Incidence and class specificity.

Gambian children with past or present Plasmodium falciparum malaria were investigated for the incidence of Coombs positivity using monospecific antisera. Approximately 50% were positive and the most frequent form of erythrocyte sensitization was with C3d. Other specificities, EIgG, EIgGC3d and EIgGC4bC3d were less common. Erthyrocytes were never found sensitized with IgA or IgM. There was no correlation between a positive test and age, tribal status or level of parasitaemia at presentation, although a positive test was often found in association with anaemia. Sensitized erythrocytes were present in the circulation for a period of up to 6 weeks following initial observation. The mechanism of erythrocyte sensitization is not known, but the results suggest a Type III complex-mediated hypersensitivity involving parasite antigen-antibody complexes. It is likely that these reactions contribute to the pathogenesis of the anaemia in falciparum malaria.

Anemia↗
PubMed1997

The human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor exists as a preformed receptor complex that can be activated by GM-CSF, interleukin-3, or interleukin-5.

The granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor is expressed on normal and malignant hematopoietic cells as well as on cells from other organs in which it transduces a variety of functions. Despite the widespread expression and pleiotropic nature of the GM-CSF receptor, little is known about its assembly and activation mechanism. Using a combination of biochemical and functional approaches, we have found that the human GM-CSF receptor exists as an inducible complex, analogous to the interleukin-3 (IL-3) receptor, and also as a preformed complex, unlike the IL-3 receptor or indeed other members of the cytokine receptor superfamily. We found that monoclonal antibodies to the GM-CSF receptor alpha chain (GMR alpha) and to the common beta chain of the GM-CSF, IL-3, and IL-5 receptors (beta(c)) immunoprecipitated both GMR alpha and beta(c) from the surface of primary myeloid cells, myeloid cell lines, and transfected cells in the absence of GM-CSF. Further association of the two chains could be induced by the addition of GM-CSF. The preformed complex required only the extracellular regions of GMR alpha and beta(c), as shown by the ability of soluble beta(c) to associate with membrane-anchored GMR alpha or soluble GMR alpha. Kinetic experiments on eosinophils and monocytes with radiolabeled GM-CSF, IL-3, and IL-5 showed association characteristics unique to GM-CSF. Significantly, receptor phosphorylation experiments showed that not only GM-CSF but also IL-3 and IL-5 stimulated the phosphorylation of GMR alpha-associated beta(c). These results indicate a pattern of assembly of the heterodimeric GM-CSF receptor that is unique among receptors of the cytokine receptor superfamily. These results also suggest that the preformed GM-CSF receptor complex mediates the instantaneous binding of GM-CSF and is a target of phosphorylation by IL-3 and IL-5, raising the possibility that some of the biologic activities of IL-3 and IL-5 are mediated through the GM-CSF receptor complex.

Animals↗