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 1,027 records · Page 57Linked to original sources
PubMed1981

The activity of an anti-allergic compound, proxicromil, on models of immunity and inflammation.

A tricyclic chromone, proxicromil (sodium 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-naphtho (2,3-b) pyran-2-carboxylate), has been tested for activity against certain immunological and inflammatory reactions. When given parenterally it suppressed the development of delayed hypersensitivity reactions in sensitized mice and guinea-pigs but did not affect the rejection of skin allografts in mice. The compound had no activity against certain in vitro correlates of delayed hypersensitivity reactions (lymphocyte transformation and lymphokine activity), but did have an inhibitory effect on lymphokine (MIF) productions at 10(-4) M but not at 10(-5) M. Proxicromil was also found to be active in non-immunologically mediated models of inflammation and in models having an immunological component which are known to be sensitive to non-steroidal anti-inflammatory drugs (adjuvant arthritis, reversed passive Arthus reaction). The activity of this compound was enhanced when administered in arachis oil when compared to its activity in saline. Proxicromil has not direct activity on the development of immune responsiveness but appear to suppress the expression of delayed hypersensitivity and immune complex mediated hypersensitivity reactions by virtue and its anti-inflammatory properties. This activity is not associated with inhibition of cyclo-oxygenase.

Animals↗
PubMed2004

Rb inhibits E2F-1-induced cell death in a LXCXE-dependent manner by active repression.

Rb (retinoblastoma protein) inhibits E2F-1-induced cell death. We now show that the ability of Rb to inhibit E2F-1-induced cell death is dependent on a functional LXCXE-binding site in Rb, thereby suggesting that proteins that bind the LXCXE-binding site in Rb may regulate the anti-apoptotic activity of Rb. HDAC1, an LXCXE protein that plays a critical role in Rb-mediated transcription repression, abrogates the effect of Rb on E2F-1-induced cell death. In contrast, RF-Cp145, another LXCXE protein, cooperates with Rb to inhibit E2F-1-induced cell death. Both proteins exert their effect in an LXCXE-dependent manner. Rb regulates E2F-induced cell death by acting upstream of p73. Rb represses the p73 promoter. Our results further suggest a model in which Rb-E2F-1 complexes mediate the anti-apoptotic activity of Rb through active repression of target genes without recruiting HDAC1.

Amino Acid Motifs↗
PubMed2005

Chromatin assembly factor Asf1p-dependent occupancy of the SAS histone acetyltransferase complex at the silent mating-type locus HMLalpha.

Transcriptional repression of the silent mating-type loci HMLalpha and HMRa in Saccharomyces cerevisiae is regulated by chromatin structure. Sas2p is a catalytic subunit of the SAS histone acetyltransferase (HAT) complex. Although many HATs seem to relieve chromosomal repression to facilitate transcriptional activation, sas mutant phenotypes include loss of SIR1-dependent silencing of HMLalpha. To gain insight into the mechanism of the SAS complex mediated silencing at HMLalpha, we investigated the expression and chromatin structure of the alpha2 gene in the HMLalpha locus. We found that deletion of SAS2 in combination with a null allele of SIR1 changed the chromatin structure of the precisely positioned nucleosome, which includes the mRNA start site of the alpha2 gene and derepressed alpha2 transcription. The Sas2p HAT domain was required for this silencing. Furthermore, chromatin immunoprecipitation analysis revealed that the SAS complex was associated with the HMLalpha locus, and ASF1 (which encodes chromatin assembly factor Asf1p), but not SIR1 and SIR2, was necessary for this localization. These data suggest that the HAT activity and ASF1-dependent localization of the SAS complex are required for SIR1-dependent HMLalpha silencing.

Acetyltransferases↗
PubMed2004

Live cell imaging of mitochondrial movement along actin cables in budding yeast.

BACKGROUND: Mitochondrial inheritance is essential for cell division. In budding yeast, mitochondrial movement from mother to daughter requires (1) actin cables, F-actin bundles that undergo retrograde movement during elongation from buds into mother cells; (2) the mitochore, a mitochondrial protein complex implicated in linking mitochondria to actin cables; and (3) Arp2/3 complex-mediated force generation on mitochondria. RESULTS: We observed three new classes of mitochondrial motility: anterograde movement at velocities of 0.2-0.33 microm/s, retrograde movement at velocities of 0.26-0.51 microm/s, and no net anterograde or retrograde movement. In all cases, motile mitochondria were associated with actin cables undergoing retrograde flow at velocities of 0.18-0.62 microm/s. Destabilization of actin cables or mutations of the mitochore blocked all mitochondrial movements. In contrast, mutations in the Arp2/3 complex affected anterograde but not retrograde mitochondrial movements. CONCLUSIONS: Actin cables are required for movement of mitochondria, secretory vesicles, mRNA, and spindle alignment elements in yeast. We provide the first direct evidence that one of the proposed cargos use actin cables as tracks. In the case of mitochondrial inheritance, anterograde movement drives transfer of the organelle from mothers to buds, while retrograde movement contributes to retention of the organelle in mother cells. Interaction of mitochondria with actin cables is required for anterograde and retrograde movement. In contrast, force generation on mitochondria is required only for anterograde movement. Finally, we propose a novel mechanism in which actin cables serve as "conveyor belts" that drive retrograde organelle movement.

Actins↗
PubMed2002

Defects in SPT16 or POB3 (yFACT) in Saccharomyces cerevisiae cause dependence on the Hir/Hpc pathway: polymerase passage may degrade chromatin structure.

Spt16/Cdc68, Pob3, and Nhp6 collaborate in vitro and in vivo as the yeast factor SPN, which is homologous to human FACT. SPN/FACT complexes mediate passage of polymerases through nucleosomes and are important for both transcription and replication. An spt16 mutation was found to be intolerable when combined with a mutation in any member of the set of functionally related genes HIR1, HIR2/SPT1, HIR3/HPC1, or HPC2. Mutations in POB3, but not in NHP6A/B, also display strong synthetic defects with hir/hpc mutations. A screen for other mutations that cause dependence on HIR/HPC genes revealed genes encoding members of the Paf1 complex, which also promotes transcriptional elongation. The Hir/Hpc proteins affect the expression of histone genes and also promote normal deposition of nucleosomes; either role could explain an interaction with elongation factors. We show that both spt16 and pob3 mutants respond to changes in histone gene numbers, but in opposite ways, suggesting that Spt16 and Pob3 each interact with histones but perhaps with different subsets of these proteins. Supporting this, spt16 and pob3 mutants also display different sensitivities to mutations in the N-terminal tails of histones H3 and H4 and to mutations in enzymes that modulate acetylation of these tails. Our results support a model in which SPN/FACT has two functions: it disrupts nucleosomes to allow polymerases to access DNA, and it reassembles the nucleosomes afterward. Mutations that impair the reassembly activity cause chromatin to accumulate in an abnormally disrupted state, imposing a requirement for a nucleosome reassembly function that we propose is provided by Hir/Hpc proteins.

Acetyltransferases↗
PubMed1991

Recombinant soluble human complement receptor type 1 inhibits inflammation in the reversed passive arthus reaction in rats.

The human CR1 was genetically engineered by site directed mutagenesis into a truncated form which was secreted from transfected Chinese hamster ovary cells. This soluble recombinant CR1 (sCR1) was purified from the supernatants of the Chinese hamster ovary cells cultured in a hollow fiber bioreactor. sCR1 inhibits the C3 and C5 convertases of the classical and the alternative pathways in vitro. The ability of sCR1 to inhibit the immune complex-mediated inflammation in vivo was tested in a rat reversed passive Arthus reaction model. Administration of sCR1 at the dermal sites reduced the Arthus vasculitis in a dose-dependent manner as judged by both gross and microscopic examination, as well as by immunohistologic localization of C3 and C5b-9 neoantigen deposits. These data suggest that sCR1 inhibits the Arthus reaction by interrupting the activation of the C cascade, hence limiting the detrimental immune complex-induced tissue damage in vivo.

Animals↗
PubMed2004

Comparison of the effect of water release on the interaction of the Saccharomyces cerevisiae TATA binding protein (TBP) with "TATA Box" sequences composed of adenosine or inosine.

The formation of sequence-specific complexes of TATA binding protein (TBP) with the minor groove of DNA results in the burial of large nonpolar surfaces and the exclusion of water from these interfaces. The release of water is thus expected to provide a significant entropic driving force for formation of the transcription-preinitiated complexes mediated by the binding of TBP to specific sequences. In this article are described equilibrium-binding studies of Saccharomyces cerevisiae TBP to 14 bp oligonucleotides bearing either the tightly bound and efficiently transcribed adenovirus major late promoter (TATAAAAG) or its inosine-substituted derivative (TITIIIIG) as a function of neutral osmolyte concentration. These two DNA sequences present the same pattern of minor groove hydrogen-bond donors and acceptors to the protein. TBP-DNA complex formation was monitored by steady-state fluorescence resonance energy transfer measurements of the oligonucleotides end-labeled with fluorescein (donor) and TAMRA (acceptor). Correct interpretation of the results obtained with the inosine-substituted sequence required careful consideration of the optical properties of the dyes as a function of osmolyte concentration to demonstrate that the relative change in the end-to-end distances for TATAAAAG- and TITIIIIG-bearing oligonucleotides is the same upon TBP binding. Although the affinity of TBP is slightly greater for the adenosine compared with the inosine-substituted TATA sequence in the absence of osmolyte, the end-to-end distances of the bound DNA in complex with TBP, the enthalpic and electrostatic components of binding, are identical within experimental precision. However, approximately 18 additional molecules of water are released upon TBP binding the TATAAAAG as compared with the TITIIIIG sequence resulting in an entropic advantage to the binding of the natural promoter sequence. These results are considered with regard to differences in the flexibility and hydration of the two DNA sequences.

Adenosine↗
PubMed1989

Autoimmune kidney disease in MRL/Mp-lpr/lpr mice inhibited by OK-432, a streptococcal preparation.

Autoimmune MRL/Mp-lpr/lpr (MRL/l) mice were treated with the immunostimulating anti-cancer drug OK-432 (a streptococcal preparation), a potent inducer of tumour necrosis factor. Treatment was initiated at 8 weeks of age, before the onset of the autoimmune disease. OK-432 prevented the development of immune complex-mediated glomerulonephritis in a dose-dependent manner, and prolonged the life in this strain of mice. At 36 weeks of age, the incidence of proteinuria was 90% in the controls, 60% in the 0.5-KE(1 KE = 0.1 mg) treatment group, and 33% in the 2.0-KE group. The 50% survival time was 23 weeks for the controls; 32 weeks for the 0.5-KE group; and greater than 36 weeks for the 2.0-KE group. Immune complex deposition in glomeruli was significantly reduced in the treated groups. The IgM class of serum autoantibody levels was significantly increased by OK-432 treatment but the IgG class was almost unchanged. Furthermore, lymphadenopathy and splenomegaly were not suppressed. The results indicate that OK-432 may be useful in the treatment of autoimmune disease in humans.

Animals↗
PubMed2002

Mast cells and inflammation.

Mast cells have long been recognized as potent producers of a large panel of biologically highly active mediators such as biogenic amines, arachidonic acid metabolites, cytokines and chemokines, but most of their biological functions have been elusive and speculative. By taking advantage of mast cell-deficient mice, the role of mast cells in a variety of experimental settings can now be studied in detail and such approaches have dramatically altered and enlarged our knowledge about mast cell biology and function. Herein we will focus on the role of mast cells in inflammatory reactions of diverse origin, such as delayed type hypersensitivity, atopy, immune complex-mediated inflammation and innate immune responses. From the current standpoint, there is no doubt that the most outstanding and beneficial feature of mast cells is their recently discovered ability to induce a life-saving inflammatory response rapidly upon encountering microbes and microbial constituents. Nevertheless, the picture is also emerging that mast cells are deeply involved in the induction and maintenance of a variety of severe allergic and autoimmune diseases. However, a deeper understanding of their activation and immune-modulatory capacity might open a new window for the development of curative strategies.

Animals↗
PubMed2004

Agonist-specific regulation of parathyroid hormone (PTH) receptor type 2 activity: structural and functional analysis of PTH- and tuberoinfundibular peptide (TIP) 39-stimulated desensitization and internalization.

The human PTH receptor type 2 (PTH2R) is activated by PTH and tuberoinfundibular peptide of 39 residues (TIP39), resulting in cAMP and intracellular Ca signaling. We now report that, despite these similarities, PTH and TIP39 elicit distinct responses from PTH2R. First, TIP39 induced beta-arrestin and protein kinase Cbeta mobilization and receptor internalization, whereas PTH did not. However, PTH stimulated trafficking of these molecules for a chimeric PTH2R containing the N terminus and third extracellular loop of PTH receptor type 1 (PTH1R). Second, whereas PTH-stimulated cAMP activity was brief and rapidly resensitized, the response to TIP39 was sustained and partly desensitized for a prolonged period. PTH2R desensitization was mediated by beta-arrestin interaction with the C terminus (amino acids 426-457) of PTH2R, whereas beta-arrestin mobilization had a minor influence on PTH2R internalization in response to TIP39, as shown with C terminus deletion mutants and/or dominant negative forms of beta-arrestin and dynamin. These data contrast with PTH1R, at which these dominant negative mutants markedly inhibited receptor internalization. Collectively, these results further highlight how specific interactions within the ligand-receptor bimolecular complex mediate distinct postactivation responses of class II G protein- coupled receptors and provide novel insights into the physiological regulation of PTH2R activity.

Amino Acid Sequence↗
PubMed1993

Specific immune complexes augment in vitro acetylcholine receptor-specific T-cell proliferation.

We investigated the interaction between acetylcholine receptor (AChR)-specific T-helper cells from patients with myasthenia gravis and murine monoclonal anti-AChR antibodies. At optimal antigen concentration, anti-AChR antibodies neither enhanced nor impaired T-cell responses. However, at substimulatory antigen concentration, addition of anti-AChR antibodies substantially enhanced the proliferation of AChR-specific T cells. In spite of low amounts of antigen, immune complex formation allowed highly efficient capture and uptake of antigen via Fc receptors on antigen-presenting cells, which could be inhibited by an antibody to Fc receptors. Immune complex-mediated stimulation of sensitized AChR-specific T lymphocytes in vivo may contribute to the exacerbation of the disease, and demonstrates the interaction between T and B lymphocytes in myasthenia gravis.

Adjuvants, Immunologic↗
PubMed2006

Differential MHC class II presentation of a pathogenic autoantigen during health and disease.

Glucose-6-phosphate isomerase (GPI) is the target autoantigen recognized by KRN T cells in the K/BxN model of rheumatoid arthritis. T cell reactivity to this ubiquitous Ag results in the recruitment of anti-GPI B cells and subsequent immune complex-mediated arthritis. Because all APCs have the capacity to process and present this autoantigen, it is unclear why systemic autoimmunity with polyclonal B cell activation does not ensue. To this end, we examined how GPI is presented by B cells relative to other immunologically relevant APCs such as dendritic cells (DCs) and macrophages in the steady state, during different phases of arthritis development, and after TLR stimulation. Although all APCs can process and present the GPI:I-A(g7) complex, they do so with different efficiencies. DCs are the most potent at baseline and become progressively more potent with disease development correlating with immune complex uptake. Interestingly, in vivo and in vitro maturation of DCs did not enhance GPI presentation, suggesting that DCs use mechanisms to regulate the presentation of self-peptides. Non-GPI-specific B cells are the weakest APCs (100-fold less potent than DCs) and fail to productively engage KRN T cells at steady state and during arthritis. However, the ability to stimulate KRN T cells is strongly enhanced in B cells after TLR ligation and provides a mechanism whereby polyclonal B cells may be activated in the wake of an acute infection.

Acute Disease↗
PubMed1989

Intravenous cyclophosphamide therapy of severe SLE.

Intravenous cyclophosphamide therapy of severe systemic lupus is associated with reduction in the numbers of circulating T and B lymphocytes, suppression of T11 (CD2) receptor-mediated responses, and suppression of autoantibody production. In clinical trials, intravenous cyclophosphamide plus moderate-to low-dose daily oral prednisone appears to reduce the rate of progression of irreversible renal injury in patients who have active nephritis and definite but limited chronic changes in biopsy specimens. It may also be effective in other forms of severe lupus, although controlled trials are lacking. It may be the treatment of choice in severe lupus characterized by ongoing antibody or immune-complex mediated tissue injury.

Acute Disease↗
PubMedDate not supplied

Glomerular lesions in HIV-infected patients: a Yale University Department of Medicine Residency Peer-Teaching Conference.

HIV-associated nephropathy (HIVAN) is a clinicopathologic entity characterized by heavy proteinuria, absence of edema and an irreversible decline in renal function. Findings on renal biopsy include: collapsed glomerular capillaries; visceral glomerular epitheliosis; microcystic tubules; mesangial prominence; and endothelial tubuloreticular inclusions. Early in the AIDS epidemic, HIVAN was the predominant glomerular lesion observed in HIV-infected patients. It is being increasingly recognized, especially in Caucasian populations, that a variety of immune complex-mediated lesions such as membranoproliferative glomerulonephritis, proliferative glomerulonephritis and IgA nephropathy are associated with HIV infection. In this review we present two cases: one patient whose first presentation of AIDS was end-stage renal disease, who on biopsy was found to have HIVAN, and the second, who was infected with HIV, and on biopsy was found to have hepatitis C-related hepatitis C related membranoproliferative glomerulonephritis. We also review the current literature on HIVAN and HIV-associated immune complex diseases (HIVICDs). Each case illustrates an important clinical point. The first that renal disease can be the first manifestation of HIV infection and the second that HIV-infected patients may develop immune complex related renal diseases, some of which may be potentially treatable.

AIDS-Associated Nephropathy↗
PubMed2006

Prevention and reversal of nephritis in MRL/lpr mice with a single injection of C-reactive protein.

OBJECTIVE: C-reactive protein (CRP) is an acute-phase serum protein with binding reactivity to nuclear autoantigens and immunomodulatory function. The MRL/lpr mouse is an important model of human systemic lupus erythematosus (SLE). These mice develop high-titer anti-DNA antibodies and immune complex-mediated nephritis and exhibit progressive lymphadenopathy. The mortality rate among these mice is 50% by age 18-20 weeks; the most frequent cause of death is glomerulonephritis. The present study was undertaken to determine whether treatment of mice with CRP would affect the course of lupus nephritis. METHODS: MRL/lpr mice were treated with a single 200-mug injection of CRP at either age 6 weeks (before disease onset) or age 13 or 15 weeks (when proteinuria had reached high levels). Proteinuria was measured weekly, and levels of anti-double-stranded DNA autoantibodies and blood urea nitrogen were determined monthly. Glomerular immune complex deposition and renal pathology were assessed in mice ages 15 weeks and 17 weeks. RESULTS: Early CRP treatment markedly delayed the onset of proteinuria and lymphadenopathy, increased survival, and reduced levels of autoantibodies to DNA. Treatment of mice with active disease reversed proteinuria and prolonged survival. Renal disease was decreased in CRP-treated mice, with a marked suppression of glomerular pathology, tubular degeneration, and interstitial inflammation, which correlated with the decrease in proteinuria and azotemia. CONCLUSION: These findings demonstrate that systemic suppression of autoimmunity is initiated by a single injection of CRP. Long-term maintenance of CRP-mediated protection was reversed by injection of an anti-CD25 monoclonal antibody but not by macrophage depletion, suggesting that disease suppression is maintained by CD25-bearing T cells.

Animals↗
PubMed1989

Involvement of eicosanoids and PAF in immune-complex alveolitis.

An immune-complex-mediated hypersensitivity reaction induced in the rat lung was followed by release of the eicosanoids thromboxane, prostaglandin E2 and leukotriene B4 into the bronchoalveolar space. Concomitantly, there was a decrease in the number of circulating platelets. The thrombocytopenia was inhibited by a cyclo-oxygenase inhibitor (indomethacin), a platelet activating factor (PAF) antagonist (BN-52021) and an inhibitor of thromboxane (econazole), but was not affected by a lipoxygenase inhibitor (NDGA). These results suggest the involvement of eicosanoids and PAF in the immune complex hypersensitivity reaction in the rat lung and indicate the occurrence of interactions between PAF and thromboxane.

Alveolitis, Extrinsic Allergic↗
PubMed1995

[Internal medicine complications of ventriculoatrial shunt].

BACKGROUND: Ventriculo-atrial shunts (VASs) and ventriculo-peritoneal shunts (VPSs) are the symptomatic treatment of choice for hydrocephalus. Bacterial contamination of the atrial part of VASs (usually with Staphylococcus epidermidis) can result in further organ complications, in most instances immune complex mediated glomerulonephritis ("shunt-nephritis") or direct microbial heart valve destruction. PATIENTS AND METHODS: In a retrospective study, we analyzed clinical and laboratory data of 11 patients with VAS associated complications as well as the course of the disease. RESULTS: The following complications were observed: glomerulonephritis (n = 9), glomerulonephritis and aortic valve destruction (n = 1), pulmonary embolism, pulmonary hypertension and tricuspid valve insufficiency (n = 1). Out of the 11 patients, 8 suffered from unexplained fever. All 11 patients had elevated circulating immune complexes. In 3 of 4 patients initially requiring dialysis, renal function improved which allowed to stop hemodialysis. Renal function also improved in 3 of 5 patients who presented with elevated serum creatinine. Unfortunately, the patient with multiple pulmonary embolisms and tricuspid valve insufficiency died of progressive pulmonary hypertension. CONCLUSION: The prognosis for impaired renal function is good only if the VAS infection is diagnosed early and an immediate surgical and antibiotic treatment leads to an eradication of the underlying chronic infection.

Adult↗
PubMed1994

Transforming growth factor-beta 1 stimulates glomerular mesangial cell synthesis of the 72-kd type IV collagenase.

Transforming growth factor-beta 1 (TGF-beta 1) is generally considered to exert positive effects on the accumulation of extracellular matrices. These occur as the net result of enhanced matrix protein synthesis, diminished matrix metalloproteinase (MMP) synthesis, and augmented production of specific inhibitors, including the tissue inhibitor of metalloproteinases (TIMP-1). Given that glomerular TGF-beta 1 synthesis is induced by inflammation, the effects of this cytokine on synthesis of the 72-kd type IV collagenase and TIMP-1 by cultured human mesangial cells were evaluated. Concentrations of TGF-beta 1 of 5 ng/ml and above specifically stimulated the synthesis of the 72-kd type IV collagenase. This effect was independent of the stimulatory effect of TGF-beta 1 on TIMP-1 synthesis, which was maximal in a lower concentration range (0.1 to 1 ng/ml). Most significantly, the net effect at the higher concentrations of TGF-beta 1 was an excess of enzyme over the TIMP-1 inhibitor. Northern blot analysis of TGF-beta 1-stimulated human mesangial cells demonstrated a specific increase in the abundance of the 3.1 kb mRNA transcript encoding the 72-kd type IV collagenase, presumably mediated by a direct stimulation of 72-kd type IV collagenase mRNA transcription observed as early as 3 hours after exposure to TGF-beta 1. These studies were extended to an analysis of the expression of TGF-beta 1 and 72-kd type IV collagenase mRNAs in normal and nephritic rats. In normal animals, basal TGF-beta 1 and 72-kd type IV collagenase mRNA expression was observed in a strictly mesangial distribution. After induction of acute immune complex-mediated glomerulonephritis, there was a major increase in TGF-beta 1 and 72-kd type IV collagenase mRNA expression, which was strictly limited to the expanded, hypercellular mesangial compartment. Enhanced synthesis of the mesangial type IV collagenase in response to TGF-beta 1 released during glomerular inflammatory processes could have an important role in the extensive glomerular matrix remodeling that accompanies these disorders.

Animals↗