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 829 records · Page 46Linked to original sources
PubMed2005

Impairment of the TFIIH-associated CDK-activating kinase selectively affects cell cycle-regulated gene expression in fission yeast.

The fission yeast Mcs6-Mcs2-Pmh1 complex, homologous to metazoan Cdk7-cyclin H-Mat1, has dual functions in cell division and transcription: as a partially redundant cyclin-dependent kinase (CDK)-activating kinase (CAK) that phosphorylates the major cell cycle CDK, Cdc2, on Thr-167; and as the RNA polymerase (Pol) II carboxyl-terminal domain (CTD) kinase associated with transcription factor (TF) IIH. We analyzed conditional mutants of mcs6 and pmh1, which activate Cdc2 normally but cannot complete cell division at restrictive temperature and arrest with decreased CTD phosphorylation. Transcriptional profiling by microarray hybridization revealed only modest effects on global gene expression: a one-third reduction in a severe mcs6 mutant after prolonged incubation at 36 degrees C. In contrast, a small subset of transcripts ( approximately 5%) decreased by more than twofold after Mcs6 complex function was compromised. The signature of repressed genes overlapped significantly with those of cell separation mutants sep10 and sep15. Sep10, a component of the Pol II Mediator complex, becomes essential in mcs6 or pmh1 mutant backgrounds. Moreover, transcripts dependent on the forkhead transcription factor Sep1, which are expressed coordinately during mitosis, were repressed in Mcs6 complex mutants, and Mcs6 also interacts genetically with Sep1. Thus, the Mcs6 complex, a direct activator of Cdc2, also influences the cell cycle transcriptional program, possibly through its TFIIH-associated kinase function.

Cell Cycle↗
PubMed1978

Pulmonary hemorrhage in systemic lupus erythematosus.

The clinicopathological features of four patients with systemic lupus erythematosus and pulmonary hemorrhage are described. Our study confirms that pulmonary hemorrhage may be a dominant clinical expression of lung involvement in this disease. Its clinical manifestations are usually quite characteristic. However, hemoptysis may be absent. Radiographically, bilateral alveolar infiltrates resembling pulmonary edema or infection may be seen. Pulmonary hemorrhage was a major contributing factor to the death of three of our patients. The possible pathogenetic mechanisms responsible for pulmonary hemorrhage in our patients and other patients previously recorded in the literature are reviewed. Evidence supporting an immune complex pathogenesis is presented. Our immunopathological and ultrastructural studies demonstrate deposition of immune aggregates in the lungs in the alveolar septa, large blood vessels, and bronchioles in a manner similar to that which has been observed in the experimental serum sickness model of immune complex mediated pulmonary injury. The histological abnormalities, although nonspecific, are consistent with this interpretation, and collectively show diffuse alveolar lining cell and endothelial cell injury. However, an immune complex pathogenesis may not completely explain the occurrence of pulmonary hemorrhage in SLE. Other factors, including bleeding disorders, pulmonary infection, oxygen toxicity, and the "shock lung" syndrome, may also have contributed to lung hemorrhage in some of these patients.

Adolescent↗
PubMed1984

Inherited complement deficiencies.

Isolated genetic deficiencies of individual components of the complementary system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for Factor I, Factor H and properdin. It is only for Factor B and Factor D of the alternative pathway that homozygous deficiency states are not so far known. Complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with Neisseria. This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation. The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them. On the other hand the strong association between complement deficiencies and immune-complex diseases--especially systemic lupus erythematosus--was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage. The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes. It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely by an immune complex mechanism. Recently described deficiencies of complement receptors and their effects in vivo are described.

Blood Donors↗
PubMed1992

Induction of interleukin 6 synthesis in mouse glomeruli and cultured mesangial cells.

Interleukin 6 (IL-6) is an autocrine growth factor of cultured mesangial cells (MC) and intraglomerular IL-6 production is suggested to be closely associated with the pathogenesis of human mesangial proliferative glomerulonephritis (mesPGN). In this study, to elucidate the mechanisms regulating the intraglomerular production of IL-6, we examined what kinds of stimuli are significant in the induction of IL-6 synthesis in vitro and in vivo. Incubation of cultured mesangial cells with interleukin 1 (IL-1) or bacterial lipopolysaccharide (LPS) induced significant IL-6 production, and intravenous injection of IL-1 or LPS into normal BALB/c mice induced significant intraglomerular IL-6 mRNA expression. Furthermore, we indicated in this study that IL-6 mRNA expression was augmented in the glomeruli of mice with immune complex-mediated glomerulonephritis.

Animals↗
PubMed1988

Macrophage-derived cytokines amplify immune complex-triggered O2-. responses by rat alveolar macrophages.

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are monocyte macrophage-derived hormonelike regulatory proteins that participate in many physiologic and pathophysiologic processes. Several proinflammatory activities have been attributed to these cytokines, but their importance in anatomically compartmentalized inflammatory processes is unclear. The current in vitro studies have been designed to examine modulatory influences of these cytokines on O2-. responses of rat phagocytes implicated as effector cells in immune complex mediated lung injury. Purified human IL-1, recombinant human TNF (rTNF), and culture supernatant from zymosan-activated alveolar macrophages significantly amplified O2-. responses of immune complex-stimulated alveolar macrophages but did not enhance the responses of neutrophils. Equivalent concentrations of IL-1, rTNF, and alveolar macrophage culture supernatant had no direct stimulatory effect on alveolar macrophages as measured by O2-. production. Culture media from unstimulated alveolar macrophages exerted negligible effects on O2-. generation by immune complex-activated alveolar macrophages. These data indicate that O2- responses of immune complex alveolar macrophages can be enhanced by the presence of IL-1, TNF, or media from activated macrophages. It is possible that macrophage products may greatly amplify tissue injury through the enhancement of oxygen radical production.

Animals↗
PubMed2003

Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation.

The IkappaB kinase (IKK) complex mediates activation of transcription factor NF-kappaB by phosphorylation of IkappaB proteins. Its catalytic subunits, IKKalpha and IKKbeta, require association with the regulatory IKKgamma (NEMO) component to gain full basal and inducible kinase activity. However, the oligomeric composition of the IKK complex and its regulation by IKKgamma are poorly understood. We show here that IKKgamma predominantly forms tetramers and interacts with IKKalpha or IKKbeta in this state. We propose that tetramerization is accomplished by a prerequisite dimerization through a C-terminal coiled-coil minimal oligomerization domain (MOD). This is followed by dimerization of the dimers with their N-terminal sequences. Tetrameric IKKgamma sequesters four kinase molecules, yielding a gamma(4)(alpha/beta)(4) stoichiometry. Deletion of the MOD leads to loss of tetramerization and of phosphorylation of IKKbeta and IKKgamma, although the kinase can still interact with the resultant IKKgamma monomers and dimers. Likewise, MOD-mediated IKKgamma tetramerization is required to enhance IKKbeta kinase activity when overexpressed in 293 cells and to reconstitute a lipopolysaccharide-responsive IKK complex in pre-B cells. These data thus suggest that IKKgamma tetramerization enforces a spatial positioning of two kinase dimers to facilitate transautophosphorylation and activation.

Biopolymers↗
PubMed1999

Alteration of G1 cell-cycle protein expression and induction of p53 but not p21/waf1 by the DNA-modifying carcinogen 2-acetylaminofluorene in growth-stimulated hepatocytes in vitro.

2-Acetylaminofluorene (AAF) is a potent tumor promoter in rat liver carcinogenesis models. In the resistant hepatocyte model, AAF is combined with a growth stimulus for efficient promotion of preneoplastic lesions. The promoting property of AAF in this model is closely associated with mito-inhibition of normal hepatocytes, an effect to which initiated cells are resistant. How AAF induces growth arrest is not known, but genotoxic as well as non-genotoxic effects have been implicated. To elucidate the mechanisms of AAF-induced mito-inhibition, we studied the expression of the tumor suppressor protein p53 and the cyclin-dependent kinase (cdk) complexes mediating G1 progression and S-phase entry. Hepatocytes were isolated from male Fisher 344 rats fed either a control diet or a diet supplemented with 0.02% AAF for 1 wk and cultured in a defined serum-free medium containing epidermal growth factor, insulin, and dexamethasone. Thymidine labeling revealed a profound inhibition of DNA synthesis in AAF-exposed cells compared with control cells. The retinoblastoma protein did not become hyperphosphorylated in AAF-exposed cells. Thus, inhibition of G1 cyclin-cdk activity was implied as a cause of growth arrest. Indeed, G1 cell-cycle arrest was accompanied by reduced induction and nuclear accumulation of the cyclin D1-cdk4 complex and inhibited nuclear translocation of cdk2. Furthermore, the growth arrest was not mediated through p21/waf1 upregulation, although nuclear levels of p53 were increased. Thus, carcinogen-induced mito-inhibition may be effected by altered levels and localization of G1 cyclin-cdk complexes, independent of the upregulation of cdk inhibitory proteins.

2-Acetylaminofluorene↗
PubMed1994

Influence of polysaccharides on neutrophil function: specific antagonists suggest a model for cooperative saccharide-associated inhibition of immune complex-triggered superoxide production.

We have previously shown that certain monosaccharides (N-acetyl-D-glucosamine and mannose) could cooperatively inhibit the ability of neutrophils to release superoxide anions in response to immune complexes. To test the possible origins of the cooperative inhibition of superoxide release, we have examined the effect of a panel of polysaccharides on superoxide release in the presence or absence of immune complexes. Although exposure to particulate beta-glucan and hyaluronan triggered superoxide release from neutrophils, other polysaccharides including chitin and mannan were without effect. Both chitin and mannan, but not other polysaccharides, inhibited the immune complex-mediated stimulation of superoxide release in a dose-dependent fashion. In sharp contrast to the cooperative inhibition mediated by monosaccharides, chitin and mannan exhibited Hill coefficients of 1. This inhibition of superoxide production was not due to simple blockage of Fc receptors since fluorescent immune complexes bound equally well to neutrophils in the presence or absence of mannan or chitin as shown by epifluorescence microscopy and quantitative fluorometry. Furthermore, this inhibition of superoxide release was not observed when neutrophils were stimulated with phorbol myristate acetate and ionophore A23187 or hyaluronan. Therefore, the specific inhibition of superoxide production by mannan and chitin could not be explained by either receptor blockage or by some nonspecific effect on cells. We suggest that these molecules interfere with a step in transmembrane signaling, presumably involving the integrin CR3. The observed Hill coefficients suggest the possibility that one polysaccharide may simultaneously bind to two monosaccharide binding sites yielding a Hill coefficient of 1, whereas individual monosaccharides separately bind yielding a Hill coefficient of 2.

Adult↗
PubMed2005

Interactions between subunits of Drosophila Mediator and activator proteins.

Mediator was first identified because of its activity in activator-stimulated transcription in vivo and in vitro. Later, biochemical fractionation led to the co-purification of the multi-subunit Mediator complex and RNA polymerase II (pol II). Results of these studies suggested a model whereby transcription-activator proteins, which bind to specific gene regulatory sequences, recruit both Mediator and pol II as a holoenzyme in a one-step mechanism. More recent studies of Drosophila Mediator and additional studies in yeast have demonstrated that different transcription activators can bind and recruit Mediator to promoters in vivo in a step that is independent of pol II recruitment. Moreover, the different activators in Drosophila bind and recruit Mediator via physical interactions with specific subsets of proteins. These features of Mediator function seem to be broadly conserved.

Animals↗
PubMedDate not supplied

Role of the central metal ion and ligand charge in the DNA binding and modification by metallosalen complexes.

Several metal complexes of three different functionalized salen derivatives have been synthesized. The salens differ in terms of the electrostatic character and the location of the charges. The interactions of such complexes with DNA were first investigated in detail by UV-vis absorption titrimetry. It appears that the DNA binding by most of these compounds is primarily due to a combination of electrostatic and other modes of interactions. The melting temperatures of DNA in the presence of various metal complexes were higher than that of the pure DNA. The presence of additional charge on the central metal ion core in the complex, however, alters the nature of binding. Bis-cationic salen complexes containing central Ni(II) or Mn(III) were found to induce DNA strand scission, especially in the presence of co-oxidant as revealed by plasmid DNA cleavage assay and also on the basis of the autoradiogram obtained from their respective high-resolution sequencing gels. Modest base selectivity was observed in the DNA cleavage reactions. Comparisons of the linearized and supercoiled forms of DNA in the metal complex-mediated cleavage reactions reveal that the supercoiled forms are more susceptible to DNA scission. Under suitable conditions, the DNA cleavage reactions can be induced either by preformed metal complexes or by in situ complexation of the ligand in the presence of the appropriate metal ion. Also revealed was the fact that the analogous complexes containing Cu(II) or Cr(III) did not effect any DNA strand scission under comparable conditions. Salens with pendant negative charges on either side of the precursor salicylaldehyde or ethylenediamine fragments did not bind with DNA. Similarly, metallosalen complexes with net anionic character also failed to induce any DNA modification activities.

Autoradiography↗
PubMed1996

Drosophila alpha-catenin and E-cadherin bind to distinct regions of Drosophila Armadillo.

Adherens junctions are multiprotein complexes mediating cell-cell adhesion and communication. They are organized around a transmembrane cadherin, which binds a set of cytoplasmic proteins required for adhesion and to link the complex to the actin cytoskeleton. Three components of Drosophila adherens junctions, analogous to those in vertebrates, have been identified: Armadillo (homolog of beta-catenin), Drosophila E-cadherin (DE-cadherin), and alpha-catenin. We carried out the first analysis of the interactions between these proteins using in vitro binding assays, the yeast two-hybrid system, and in vivo assays. We identified a 76-amino acid region of Armadillo that is necessary and sufficient for binding alpha-catenin and found that the N-terminal 258 amino acids of alpha-catenin interact with Armadillo. A large region of Armadillo, spanning six central Armadillo repeats, is required for DE-cadherin binding, whereas only 41 amino acids of the DE-cadherin cytoplasmic tail are sufficient for Armadillo binding. Our data complement and extend results obtained in studies of vertebrate adherens junctions, providing a foundation for understanding how junctional proteins assemble and a basis for interpreting existing mutations and creating new ones.

Amino Acid Sequence↗
PubMed2003

Recombinant congenic strains of mice: a new tool for the genetic dissection of efficacy and toxicity of adjuvants.

The efficacy of immunization of a vaccine depends on an antigen, an adjuvant, and on the expression of multiple genes in the host. The responsiveness of various strains of mice to adjuvants is therefore dependent on their genetic background present as a complex, multigenic trait similarly as in man. We have recently developed a gene-discovery platform, termed recombinant congenic strains (RCS), that greatly facilitates the dissection, localization and characterization of genes that mediate complex traits such as responsiveness to adjuvants. These recombinant congenic mice, which were constructed from two progenitor strains (A/J and C57BL/6) that are phenotypically different for several spontaneous or infectious diseases, were generated such that they carry 13.5% of the one genome in 85% of the other genome. The use of these RCS mice therefore enables a more efficient identification of genes that mediate the responsiveness of the adjuvant.

Adjuvants, Immunologic↗
PubMed1996

Experimental myocarditis in the guinea-pig.

In guinea-pigs, myocarditis was induced under experimental conditions by immunizing the animals with rabbit skeletal muscle myosin-beta. The salient histopathological features were foci of perivascular lymphonononuclear aggregates, necrosis, and degeneration of myocardial cells. Antimyosin-beta antibodies in the immune complexes were demonstrated in the sera of the guinea-pigs. An immune-complex-mediated tissue-injury is proposed in the pathogenesis of myocarditis.

Animals↗
PubMed1993

Adhesive interactions in thymic development: does selective expression of CD45 isoforms promote stage-specific microclustering in the assembly of functional adhesive complexes on differentiating T lineage lymphocytes?

CD45 isoform transitions appear to play essential roles in both life and death, and correlate with the stages of thymocyte development during which there is a change in physical location from medullary and/or outer cortical areas to the inner cortex. This work speculates that CD45 isoforms, through a focal role in the assembly of adhesive complexes mediated by the external domains, participate in the maintenance and/or modulation of migratory behaviour by differentiating thymocytes, or alternatively in the anchoring of thymocytes in a generative micro-environment. The objective of the sections that follow is to formulate the hypothesis that CD45 isoforms, through their differential interactions with adhesion molecules expressed by T cells, profoundly influence cell motility and consequent micro-environmental localization. An adhesive assembly of CD45 and adhesion molecules on the outside, and of the adhesive complex with the cytoskeleton on the inside, would promote CD45-mediated regulation of adhesion/de-adhesion through lateral external interactions mediated by external domains of CD45 isoforms, through enzymatic modulation of the cytoplasmic domains of adhesion molecules by the CD45 tyrosine phosphatase activity, and through phosphatase control of cytoskeletal assembly and disassembly.

Animals↗
PubMed1983

Factors related to the initiation and recurrence of uveitis. XL Edward Jackson memorial lecture.

Uveitis comprises a complex group of diseases in which morbidity may depend on the nature of the initial inflammation as well as on the genetic, hormonal, and emotional background of the patient. Uveitis is initiated in every instance by some form of tissue injury. This may occur as an attack on individual cells by organisms such as Toxoplasma gondii or Herpesvirus hominis. Autoimmune disease may be produced as a late result of microbe-induced injury. The development of specific forms of autoimmunity seems to be dependent upon genetic as well as hormonal factors, particularly estrogens. Tissue injury of immunologic origin takes several forms, such as cytotoxic damage from sensitized lymphocytes, immune complex-mediated injury, and injury from the oxidative products of inflammatory cells. In some cases, permanent alteration of uveal vascular permeability results. Recurrent uveitis may be attributed in some instances to the reappearance of infectious organisms in the target tissue. In other cases, recurrence of inflammation may be attributed to the localization of immune complexes in the uveal tract. Changes in immunoregulation can be attributed to pregnancy, aging, and emotional factors. Neurohumoral pathways related to stress-mediated changes in immunoregulation have recently been described in laboratory animals. These pathways may be linked with stress-related recurrences of uveitis in humans.

Aged↗
PubMed1992

[Subacute progressive polyneuropathy syndrome in HIV infection. The efficacy of immunosuppressive treatment?].

A subacute advanced severe sensorimotor polyneuropathy developed over 6 months in a 47-year-old patient in stage 5 of an HIV infection (Walter Reed Hospital classification). Clinical examination, cranial computed tomography and spinal nuclear magnetic imaging failed to demonstrate any central nervous system complication. Cerebrospinal fluid showed a lymphocytic pleocytosis of 57/3 cells and total protein raised to 132 mg/dl as sign of an abnormal blood-brain barrier. Circulating immune complex in blood was raised to 30%. Assuming an immune-complex mediated neuropathy treatment with oral steroids was started, initially 150 mg daily. The signs of polyneuropathy regressed almost completely, even after prednisolone was discontinued. The proportion of circulating immune complexes in blood fell within 7 weeks to 10% during this treatment. It is suggested that in HIV-infected patients severe polyneuropathies may develop as part of a humoral immune reaction in which immunosuppressive treatment can be effective. Even in advanced HIV infection high-dosage and prolonged steroid treatment can be undertaken, under strictest indications, and may have impressive results.

Acute Disease↗
PubMed2006

Minimal residual disease in ovarian cancer as a target for complement-mediated mAb immunotherapy.

Ovarian cancer is potentially well suited for local monoclonal antibody (mAb) immunotherapy, because it remains within the peritoneal cavity for a long period of time before giving rise to distant metastases. At the stage of minimal residual disease, the cells appear to be in a state of dormancy (G(0)) or at least have lower rates of tumour cell proliferation. They should be a promising target for immunotherapy. Here we first examined the cell-cycle expression of CD59 and decay-accelerating factor (DAF; CD55) on four different ovarian carcinoma cell lines, using simultaneous flow cytometric analysis of DNA content or the cell-cycle-specific nuclear proliferation protein Ki67 and CD59 or DAF surface expression. We found that CD59 and DAF are stably expressed throughout the cell cycle. The polyvalent approach to target-independent antigens to improve the efficiency of mAb complement (C)-mediated damages was promising, and tumour cells become sensitive to C damage, when incubated with cross-linked mAb against different tumour-associated antigens. Although, such immune complex-mediated C activation was rather ineffective in killing the cells, it could be potentiated by the addition of blocking mAb against CD59 and DAF. Our results suggest that the activities of intrinsic C regulators must be neutralized to make minimal residual disease a promising target for antibody therapy.

Adenocarcinoma↗
PubMed1994

Influenza virus hemagglutinin induces differentiation of mature resting B cells and growth arrest of immature WEHI-231 lymphoma cells.

We have investigated the functional requirements for the B cell "mitogenicity" of the influenza virus hemagglutinin (HA). Murine B cell proliferative responses were inducible by either infectious or inactivated virus, and by infected, paraformaldehyde-fixed cells. Viruses of the 12 different HA-subtypes displayed marked differences in their activation potential, classifying them as high (H2, H4, H6, H12), medium (H3, H5, H8, H9), or low (H1, H7, H10, H11) B cell activators. HA-mediated proliferation of resting B cells induced a vigorous Ig synthesis, with a predominance of IgG2b, IgG3, and IgM production. In this activation mode the B cell receptor (BCR) complex seems to be involved because 1) virus-triggered B cell proliferation was blocked by anti-Ig Abs, 2) B cell responses could be competitively inhibited by unfractionated high dose Igs, and 3) addition of BCR-modulating anti-CD45 mAb abrogated subsequent stimulation by HA. Furthermore, 4) influenza viruses were able to induce a growth arrest in the anti-mu sensitive B cell line WEHI-231. Most interestingly, the "tolerogenic" capacity correlated with the B cell stimulatory subtype of the virus, because highly stimulatory HA-subtypes were highly "tolerogenic" whereas low stimulatory subtypes were only marginally effective. Collectively, these observations raise the hypothesis that influenza viruses can cause polyclonal proliferation/differentiation of mature B cells and inactivation/tolerance induction in immature B cells by a mechanism that seems to mimic certain aspects of the physiologic BCR complex-mediated B cell activation.

Animals↗