Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mediator Complex”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,063 records · Page 59Linked to original sources
PubMed1997

Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF.

The vertebrate transcription factors TCF (T cell factor) and LEF (lymphocyte enhancer binding factor) interact with beta-catenin and are hypothesized to mediate Wingless/Wnt signaling. We have cloned a maternally expressed Drosophila TCF family member, dTCF. dTCF binds a canonical TCF DNA motif and interacts with the beta-catenin homolog Armadillo. Previous studies have identified two regions in Armadillo required for Wingless signaling. One of these interacts with dTCF, while the other constitutes a transactivation domain. Mutations in dTCF and expression of a dominant-negative dTCF transgene cause a segment polarity phenotype and affect expression of the Wingless target genes engrailed and Ultrabithorax. Epistasis analysis positions dTCF downstream of armadillo. The Armadillo-dTCF complex mediates Wingless signaling as a bipartite transcription factor.

Amino Acid Sequence↗
PubMed2005

The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells.

Mast cell-mediated responses are likely to be regulated by the cross talk between activatory and inhibitory signals. We have screened human cord blood mast cells for recently characterized inhibitory receptors expressed on NK cells. We found that IRp60, an Ig superfamily member, is expressed on human mast cells. On NK cells, IRp60 cross-linking leads to the inhibition of cytotoxic activity vs target cells in vitro. IRp60 is constitutively expressed on mast cells but is down-regulated in vitro by the eosinophil proteins major basic protein and eosinophil-derived neurotoxin. An immune complex-mediated cross-linking of IRp60 led to inhibition of IgE-induced degranulation and stem cell factor-mediated survival via a mechanism involving tyrosine phosphorylation, phosphatase recruitment, and termination of cellular calcium influx. To evaluate the role of IRp60 in regulation of allergic responses in vivo, a murine model of allergic peritonitis was used in which the murine homolog of IRp60, LMIR1, was neutralized in BALB/c mice by mAbs. This neutralization led to a significantly augmented release of inflammatory mediators and eosinophilic infiltration. These data demonstrate a novel pathway for the regulation of human mast cell function and allergic responses, indicating IRp60 as a candidate target for future treatment of allergic and mast cell-associated diseases.

Animals↗
PubMed2026

rRNA expansion segments mediate ribosome dimerization as a conserved stress response.

Inhibition of messenger RNA translation is a common feature in proteostatic stress cellular responses. Puromycin, a widely used compound for studying translation, disrupts protein synthesis by mimicking the 3' end of aminoacyl-transfer RNAs. Despite its extensive use as a research tool to probe the connection between translation activity and various physiological and pathological states, the cellular response associated with puromycin-induced translation stress remains incompletely understood. Here, we used electron tomography and topology analysis to define the effects of puromycin on the translation machinery in situ. We show that puromycin-treated neuronal cells exhibit an accumulation of eIF5A-bound ribosomes in a translationally inactive "idle" state, and thereby defining a broader role of eIF5A in ribosome homeostasis. Additionally, the idle ribosomes formed dimeric complexes mediated by ribosomal RNA expansion segments, suggesting an evolved mechanism involving these regions in translational hibernating and protecting idle ribosomes. We further show that the hibernating disome formation is not unique to puromycin administration but represents a conserved mechanism as a response to different cellular stressors including endoplasmic reticulum stress and amino acid depletion. Collectively, our findings illuminate distinct states of mammalian ribosome hibernation and dimerization, providing new insights into the relationship of cellular stress and the dynamic regulation of ribosomal activity.

Ribosomes↗
PubMed1984

Behçet's syndrome: immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy.

Immune regulatory dysfunction, circulating immune complexes (CIC), and polymorphonuclear (PMN) cell migration were investigated in patients with Behçet's syndrome. Six patients meeting rigorous clinical criteria were evaluated. Only one patient showed evidence of immune regulatory dysfunction (increased T4/T8 ratio). Although C1q binding and Raji cell assays for CIC yielded positive results in only one of five patients, all five patients had in vivo "histamine trap test" evidence of CIC (all controls had normal results). Sera from all Behçet's syndrome patients increased migration of neutrophils to zymosan-activated serum. Colchicine therapy abolished the enhancing effect of the patient's sera on movement of PMN cells from patients and controls. An immune complex-mediated injury that is followed by an excessive accumulation of PMN cells may lead to the cutaneous lesions and other lesions in Behçet's syndrome. Further evaluation of colchicine therapy is warranted on the basis of these studies.

Adult↗
PubMed1985

Formation of soluble immune complexes by complement in sera of patients with various hypocomplementemic states. Difference between inhibition of immune precipitation and solubilization.

To examine whether the ability of complement to form soluble immune complexes plays a role in preventing immune complex-mediated diseases, we analyzed the capacity of complement to inhibit immune precipitation (IIP) and to solubilize preformed immune aggregates (SOL) in 23 sera of patients with various hypocomplementemic states, and we correlated the results of these studies with the clinical syndromes found in the various patients. In sera with deficiency or depletion of early classical pathway components, IIP was profoundly altered, whereas SOL was delayed but in the normal range. In contrast, in sera with C3 depletion but intact classical pathway and in properdin-deficient serum, IIP was initially preserved, whereas SOL was abolished. Since the incidence of immune complex diseases in various hypocomplementemic states correlates with the severity of IIP defects, but not with reduced SOL, it is suggested that IIP is an essential biological function of complement that prevents the rapid formation of insoluble immune complexes in vivo.

Antigen-Antibody Complex↗
PubMedDate not supplied

[Drosophila genes that encode LIM-domain containing proteins: their organization, functions, and interactions].

Diverse sets of developmental programs including cytoskeleton organization, cell lineage specification, muscle and neuron differentiation, limb and eye formation, imaginal disk development are controlled by LIM-homeobox genes encoding LIM-homeodomain (LIM-HD) transcription factors. LIM-domains are known as adaptors and functional modifiers of the protein-protein interactions and of the specific contacts between the members of functional complexes mediating activation of some constitutive proteins. Primary structure of LIM-HD proteins is remarkably evolutionary conserved in vertebrates and invertebrates. Though the genome size of Drosophila is about 5 % of the mammal genome the majority of its gene families and signaling pathways are similar to those of the mammals. There are some well known LIM-domain-containing proteins in Drosophila: Arrowhead, Apterous, Islet, dLim and Lim3 transcription factors; DLMO and Prickle proteins, as well as Chip, RLIM, Ssdp cofactors that modulate the LIM-HD function. Drosophila is a unique model system to analyze genetic interactions and transcription complexes in vivo. Genetic and molecular approaches including isolation of extragenic supressors of mutations in LIM-HD proteins may be used for identification of target genes which interact directly with LIM-HD proteins and that are necessary for specification of cell identity.

Animals↗
PubMed1980

A renal lesion in ankylosing spondylitis.

2 patients with ankylosing spondylitis (A Sp) were found to have renal lesions similar to those seen in IgA nephropathy. In 1 patient the changes were extremely severe and progressive and in the other they were mild. Vascular changes were also noted in 1 patient. The findings suggest an immune complex mediated glomerulonephritis and support an earlier report that there may be a specific renal lesion in patients with A Sp. The significance of IgA deposition in the mesangium, and of an increase in the serum levels of IgA in some patients with A Sp is unclear.

Adult↗
PubMed1979

Membranous glomerulonephritis in congenital syphilis.

The glomerulonephritis of congenital syphilis is thought to be immune-complex mediated. We describe a case of C. S. in whom the only manifestation was a glomerulonephritis. Immunopathogenic studies allowed the identification of treponemal antigen in glomeruli. The elution of immunoglobulins from renal tissue showed that glomerular deposits contained antitreponemal antibodies. Cryoglobulins with antitreponemal activity were also isolated from the patient's serum.

Antibodies, Bacterial↗
PubMed1996

A functional analysis of recombinant soluble CD46 in vivo and a comparison with recombinant soluble forms of CD55 and CD35 in vitro.

The human cell surface complement regulatory proteins CD46 (MCP), CD55 (DAF) and CD35 (CR1) protect autologous cells from complement-mediated damage by inhibiting C3 and C5 convertases. This regulatory potential has previously been exploited in the treatment of some models of inflammatory injury by the generation of recombinant soluble (rs) proteins, such as rsCD55 and rsCD35 . More recently, we have shown that rsCD46 inhibits complement activation in the fluid phase. In this report, the ability of rsCD46, rsD55 and rsCD35 to regulate human complement activation mediated by the classical pathway in vitro was clearly demonstrated by all three soluble proteins; however, rsCD35 was a more effective inhibitor than either rsCD46 or rsCD55. A combination of rsCD46+ rsCD55 was more potent than either of these proteins alone. Cell lysis via alternative pathway activation in vitro was efficiently regulated by rsCD46 and rsCD35 to a similar extent, whereas rsCD55 was not effective. Assays of rsCD46 in vivo have previously not been possible due to difficulties in expressing sufficient quantities of protein. This limitation has been overcome and now we report the ability of rsCD46 to inhibit immune complex-mediated inflammation in a rat using the reverse passive Arthus reaction model. Administration of rsCD46 significantly reduced the size of lesion, and histological examination showed a reduction in inflammatory infiltrate and edema. These data suggest that rsCD46, in addition to rsCd55 and rsCD35, may be useful a therapeutic agent.

Animals↗
PubMed1996

Additive effects of suboptimal doses of estrogen and cortisone on the suppression of T lymphocyte dependent inflammatory responses in mice.

Many immune-mediated inflammatory diseases are treated with corticosteroids. This type of treatment is, however, often afflicted with side-effects such as osteoporosis and atherosclerosis. During the last decades also sex steroids, such as estrogens, have been shown to have immunoregulatory properties. In this report we studied the effect of combined treatment with suboptimal doses of dexamethasone and estradiol on T lymphocyte mediated delayed type hypersensitivity (DTH), granulocyte-mediated inflammatory responses, immunoglobulin production and antigen specific antibody responses in mice. The results show that the two hormones display additive effects on suppression of DTH. In contrast, such additive effects were not observed in granulocyte-mediated inflammation. B lymphocyte activity, measured by immunoglobulin production and antigen-specific antibody responses, were increased after exposure to estradiol and suppressed by dexamethasone. In mice treated with both hormones the up regulation of B lymphocytes was still evident. The results could indicate the potential to use combinations of corticosteroids and estrogen in the treatment of T lymphocyte dependent rheumatic diseases such as rheumatoid arthritis (RA). In addition, the B lymphocyte stimulation by estrogen in cortisone exposed mice stimulate to future studies in humans if estrogen containing contraceptives or post menopausal hormone treatment could have triggering effects in patients with immune complex mediated diseases also when they are on corticosteroid treatment.

Animals↗
PubMed1992

Beta-cell antigen-specific lysis of macrophages by CD4 T-cell clones from newly diagnosed IDDM patient. A putative mechanism of T-cell-mediated autoimmune islet cell destruction.

Immunophenotyping of the early lesion in the pancreatic islets of Langerhans demonstrates a predominance of CD4+ lymphocytes, which may be preceded by an increase in islet macrophages. This observation implies that both types of cells may be involved in autoimmune-mediated beta-cell destruction leading to IDDM. In an attempt to attribute a role to beta-cell antigen-specific CD4-expressing T-cell clones recently isolated from a newly diagnosed IDDM patient, we investigated whether such CD4 T-cells may be pathogenic in an in vitro cytotoxicity assay with HLA-DR-matched antigen-presenting macrophages as target. We report herein that, indeed, beta-cell antigen-specific CD4+ T-cells are capable of lysing macrophages in an antigen-specific fashion. This cytotoxicity is HLA-DR restricted, T-cell receptor complex mediated, and CD4 dependent. These observations imply that both helper T-cells and macrophages may be involved in the disease process via interaction between T-cells and macrophages pulsed with beta-cell antigen.

Animals↗
PubMed1998

Novel pathways, membrane coats and PI kinase regulation in yeast lysosomal trafficking.

Analysis of membrane transport in the yeast Saccharomyces cerevisiae continues to provide important insights into the molecular mechanisms that direct endocytic and lysosomal sorting pathways in eukaryotic cells. Recent findings include the identification of two novel endomembrane transport pathways, a Golgi-to-vacuole biosynthetic pathway requiring the adaptor protein-3 (AP-3) complex, and a vacuolar membrane recycling pathway regulated by PtdIns(3,5)P2. At the molecular level, a candidate vesicle coat protein complex mediating endosome-to-Golgi recycling has been identified. In addition, protein sorting signals directing phosphorylation-dependent ubiquitination of endocytic cargoes, and a recognition motif for AP-3-dependent sorting have been characterized. Important mechanistic insights into SNARE-mediated, NSF-dependent membrane fusion reactions also have been made using yeast-based in vitro assays and the identification of the zinc-binding FYVE domain as a PtdIns(3)P-specific binding domain has linked phosphoinositide signaling to the regulation of vesicle docking/fusion, as well as other membrane transport reactions along the lysosomal sorting pathways.

Adaptor Protein Complex alpha Subunits↗
PubMed1998

Lysis of plasma clots by urokinase-soluble urokinase receptor complexes.

Single-chain urokinase plasminogen activator (scuPA), the unique form secreted by cells, expresses little intrinsic plasminogen activator activity. scuPA can be activated by proteolytic cleavage to form a two-chain enzyme (tcuPA), which is susceptible to inhibition by plasminogen activator inhibitor type I (PAI-1). scuPA is also activated when it binds to its cellular receptor (uPAR), in which case the protein remains as a single chain molecule with less susceptibility to PAIs. Fibrin clots are invested with PAI-1 derived from plasma and from activated platelets. Therefore, we compared the fibrinolytic activity of complexes between scuPA and recombinant soluble uPAR (suPAR) to that of scuPA, tcuPA, and tcuPA/suPAR complexes. scuPA/suPAR complexes mediated the lysis of plasma-derived fibrin clots 14-fold more extensively than did equimolar concentrations of scuPA and threefold more extensively than did tcuPA or tcuPA/suPAR, respectively. The enhanced catalytic activity of scuPA/suPAR required that all three domains of the receptor be present, correlated with its PAI-1 resistance, was not dependent on fibrin alone, and required a plasma cofactor that was identified as IgG. Human IgG bound specifically to suPAR and scuPA/suPAR as determined by using affinity chromatography and immunoprecipitation. Plasma depleted of IgG lost most of its capacity to promote the fibrinolytic activity of scuPA/suPAR, and the activity of the complex was restored by adding plasma concentrations of purified IgG. These studies indicate that scuPA/suPAR can function as a plasminogen activator in a physiological milieu.

Amino Acid Sequence↗
PubMed1988

Reticuloendothelial clearance in cystic fibrosis and other inflammatory lung diseases.

To examine the possible pathophysiologic role of circulating immune complexes in patients with cystic fibrosis and other inflammatory lung diseases, we studied the reticuloendothelial clearance of IgG-sensitized autologous erythrocytes in 15 patients with cystic fibrosis, 6 with chronic obstructive lung disease not related to cystic fibrosis, 7 with immunodeficiencies, 5 with systemic lupus erythematosus, 4 who had previously undergone a splenectomy, and 10 normal subjects. Patients with chronic inflammation and recurrent infections (i.e., those with cystic fibrosis, chronic obstructive lung disease, and immunodeficiencies) had significantly faster clearance rates (P less than 0.05, less than 0.01, and less than 0.005, respectively) than normal subjects. In contrast, patients with systemic lupus erythematosus (a classic immune complex-mediated disease) and those who had undergone a splenectomy had delayed clearance. The accelerated reticuloendothelial clearance in patients with chronic inflammatory pulmonary disease associated with cystic fibrosis was similar to that observed in stimulated laboratory animals. The rapid clearance rate may account for the rareness of septicemia in such patients despite chronic, persistent local bacterial infection.

Adolescent↗
PubMed1998

p53 inhibits hypoxia-inducible factor-stimulated transcription.

p53 is required for hypoxia-induced apoptosis in vivo, although the mechanism by which this occurs is not known. Conversely, induction of the hypoxia-inducible factor-1 (HIF-1) transactivator stimulates transcription of a number of genes crucial to survival of the hypoxic state. Here we demonstrate that p53 represses HIF-1-stimulated transcription. Although higher levels of p53 are required to inhibit HIF than are necessary to transcriptionally activate p53 target genes, these levels of p53 are similar to those that stimulate cleavage of poly(ADP-ribose) polymerase, an early event in apoptosis. Transfection of full-length p300 stimulates both p53-dependent and HIF-dependent transcription but does not relieve p53-mediated inhibition of HIF. In contrast, a p300 fragment, which binds to p53 but not to HIF-1, prevents p53-dependent repression of HIF activity. Transcriptionally inactive p53, mutated in its DNA binding domain, retains the ability to block HIF transactivating activity, whereas a transcriptionally inactive double point mutant defective for p300 binding does not inhibit HIF. Finally, depletion of doxorubicin-induced endogenous p53 by E6 protein attenuates doxorubicin-stimulated inhibition of HIF, suggesting that a p53 level sufficient for HIF inhibition can be achieved in vivo. These data support a model in which stoichiometric binding of p53 to a HIF/p300 transcriptional complex mediates inhibition of HIF activity.

Breast Neoplasms↗
PubMed2006

Unexpected development of autoimmunity in BAFF-R-mutant MRL-lpr mice.

BAFF-R is the predominant receptor that mediates B-cell activating factor (BAFF)-dependent B-cell signalling and plays a critical role in late-stage B-cell maturation and survival. BAFF has been implicated in the development of autoimmunity and systemic lupus erythematosus (SLE). To define the role of BAFF-R in autoimmunity and SLE, we crossed A/WySnJ mice with MRL-lpr mice and generated BAFF-R-mutant MRL-lpr mice. The BAFF-R mutation markedly impaired the development of immature, mature and marginal zone B cells in the spleens of MRL-lpr mice. Unexpectedly, the BAFF-R mutation in MRL-lpr mice did not result in decreased autoantibody production, hypergammaglobulinaemia or immune complex-mediated glomerulonephritis. Rather, the ability of BAFF-R-mutant lpr splenic B cells to produce immunoglobulins in vitro was not decreased, although germinal centre formation, antibody response and B-cell proliferation were impaired. Further studies found increased numbers of B cells in the bone marrow of BAFF-R-mutant MRL-lpr mice compared to the BAFF-R-intact lupus mice. ELISPOT analysis revealed that BAFF-R-mutant MRL-lpr mice had more antibody-secreting cells in their bone marrow than the control mice. Thus, these findings could explain the development of autoimmunity and hypergammaglobulinaemia observed in BAFF-R-mutant MRL-lpr mice.

Animals↗
PubMed2003

SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells.

p130 is a member of the retinoblastoma family of pocket proteins, which includes pRB and p107. Unlike pRB and p107, p130 protein levels decrease dramatically following its hyperphosphorylation starting in the mid-G1 phase of the cell cycle. However, the mechanism leading to p130 downregulation is unknown. We have found that the proteasome inhibitor, lactacystin, inhibited p130 downregulation in T98G cells progressing through the G1/S transition and S phase and that p130 is multiubiquitylated in 293 cells. We have previously shown that ectopic expression of both cyclin D and E induces phosphorylation and downregulation of p130. Since the SKP1/Cul1/SKP2 E3 ubiquitin ligase complex mediates ubiquitylation of substrates previously phosphorylated by cyclin-dependent kinases, we investigated the potential role of this ubiquitin ligase in mediating p130 downregulation. We found that p130 interacts with SKP1, Cul-1 and SKP2 in human 293 cells. We also found that ectopic coexpression of SKP2 and p130 leads to dose-dependent downregulation of p130, reduces p130 protein half-life and induces p130 ubiquitylation in these cells. Moreover, adenoviral-mediated expression of SKP2 accelerates downregulation of endogenous hyperphosphorylated p130 in mitogen-stimulated T98G cells and primary WI38 fibroblasts. We conclude that p130 is a substrate of the SCF(SKP2) ubiquitin ligase and this E3 ligase regulates p130 abundance during the cell cycle.

Cell Cycle Proteins↗
PubMed1986

Plasma concentrations of complement split product C3d and immune complexes after procainamide induced production of antinuclear antibodies.

Seventeen patients treated with procainamide for cardiac ventricular arrhythmias were followed for up to 40 weeks. Immunological data as a clue to developing the systemic lupus erythematosus (SLE)-like syndrome was emphasized. Ten patients developed antinuclear antibodies (IgG or IgM), but no increase in the plasma concentration of the complement split product C3d or immune complexes, measured by two different methods, was demonstrated. This finding is in contrast to the high levels of both C3d and immune complexes in SLE. The discrepancy may be caused by a lack of immune complex mediated complement activation by the procainamide induced antibodies, or may be due to a difference in severity of disease. The acetylator phenotype of the patients was determined but due to the low frequency of fast acetylators no comparison of the immunological response of the two phenotypes could be done.

Aged↗