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PubMed2004

Alcohol expectancy mediation of biopsychosocial risk: complex patterns of mediation.

Alcohol expectancies' mediation of many known antecedents' influence on drinking has been well established, but most models have omitted theoretically relevant mediational pathways through both common (overlapping) and unique (nonshared) expectancy variance. The authors of this study evaluated expectancy mediation using a hierarchical expectancy model that specified both common and unique expectancy factors. The hierarchical model mediated a significantly (p <.05) larger percentage of the antecedent influences than a model specifying only common expectancy variance, revealed previously unseen mediational paths, and showed, to the authors' knowledge for the first time, expectancy mediation of protective as well as risk-related antecedents. It also allows the modeling of specific pathways for particular antecedents, rather than treating all expectancy mediation as though it flows through a general expectancy factor.

Adaptation, Psychological↗
PubMed1999

Activator-specific requirement of yeast mediator proteins for RNA polymerase II transcriptional activation.

The multisubunit Mediator complex of Saccharomyces cerevisiae is required for most RNA polymerase II (Pol II) transcription. The Mediator complex is composed of two subcomplexes, the Rgr1 and Srb4 subcomplexes, which appear to function in the reception of activator signals and the subsequent modulation of Pol II activity, respectively. In order to determine the precise composition of the Mediator complex and to explore the specific role of each Mediator protein, our goal was to identify all of the Mediator components. To this end, we cloned three previously unidentified Mediator subunits, Med9/Cse2, Med10/Nut2, and Med11, and isolated mutant forms of each of them to analyze their transcriptional defects. Differential display and Northern analyses of mRNAs from wild-type and Mediator mutant cells demonstrated an activator-specific requirement for each Mediator subunit. Med9/Cse2 and Med10/Nut2 were required, respectively, for Bas1/Bas2- and Gcn4-mediated transcription of amino acid biosynthetic genes. Gal11 was required for Gal4- and Rap1-mediated transcriptional activation. Med11 was also required specifically for MFalpha1 transcription. On the other hand, Med6 was required for all of these transcriptional activation processes. These results suggest that distinct Mediator proteins in the Rgr1 subcomplex are required for activator-specific transcriptional activation and that the activation signals mediated by these Mediator proteins converge on Med6 (or the Srb4 subcomplex) to modulate Pol II activity.

Amino Acid Sequence↗
PubMed2006

E1A is the component of the MHC class I enhancer complex that mediates HDAC chromatin repression in adenovirus-12 tumorigenic cells.

In adenovirus-12 tumorigenic cells, the viral E1A-12 protein mediates transcriptional down-regulation of the major histocompatibility complex (MHC) class I genes by targeting the class I enhancer. Here, we demonstrate by a combination of antisense and chromatin immunoprecipitation (ChIP) analysis that E1A-12 is a physical component of the class I enhancer repression complex, known to comprise COUP-TFII and histone deacetylase 1 (HDAC1). Significantly, E1A antisense was shown to co-eliminate E1A-12 as well as HDAC1 and HDAC8, but not HDAC3, from the enhancer repression complex. Consistent with elimination of HDAC1 and HDAC8, E1A antisense also resulted in a dramatic increase in histone acetylation, a hallmark of transcriptionally active chromatin. Importantly, MHC class I antigen expression was restored on the surface of E1A antisense-transfected cells. These results demonstrate that E1A-12 is associated with the MHC class I complex and apparently mediates class I transcriptional down-regulation by enacting chromatin repression through HDAC1 and HDAC8.

Adenoviridae↗
PubMed1982

A dopamine-acetylcholine link in the caudate-putamen complex which mediates metabolic rate.

In order to investigate the possible involvement of the dopaminergic and the cholinergic neurons of caudate-putamen complex (CP) in temperature regulation, we have assessed the effects of administration of either acetylcholine (Ach), atropine (Ach receptor antagonist), apomorphine (DA receptor agonist), or haloperidol (DA receptor antagonist) into the CP on metabolic, respiratory, vasomotor and temperature responses in conscious rats at various ambient temperature (Ta). The results show that intra-CP injection of either Ach or apomorphine caused hypothermia, decreased metabolism and cutaneous vasoconstriction at Ta 8 and 22 degrees C, as well as hyperthermia and cutaneous vasoconstriction at Ta 30 degrees C. On the other hand, intra-Cp injection of either atropine or haloperidol caused hyperthermia, increased metabolism and cutaneous vasoconstriction at all Ta (8, 22, and 30 degrees C) studied. There was no change in respiratory evaporative heat loss in response to these agents at all Ta studied. Furthermore, the Ach-induced hypothermia or hypo-metabolism was antagonized by pretreatment with atropine, but not with haloperidol. However, the apomorphine-induced hypothermia or hypo-metabolism at Ta 8 and 22 degrees C was antagonized by pretreatment with either atropine or haloperidol. These observations tend to indicate that a dopamine-acetylcholine link occurs in the caudate-putamen complex which mediate metabolic rate in the rat.

Acetylcholine↗
PubMed2001

Mediator--a universal complex in transcriptional regulation.

The Mediator complex is essential for basal and regulated expression of nearly all RNA polymerase II-dependent genes in the Saccharomyces cerevisiae genome. Mediator acts as a bridge, conveying regulatory information from enhancers and other control elements to the promoter. It is now clear that Mediator-like complexes also exist in higher eukaryotic cells and that they have an important role in metazoan transcriptional regulation. However, the exact mechanism of Mediator-dependent transcriptional regulation remains unclear. We review here some recent advances in our understanding of Mediator structure and function. We also discuss a model to account for the functional and evolutionary relationship between yeast and metazoan Mediators. As an appendix to this review, we have created a database, MEDB, in which we have compiled information about all the S. cerevisiae Mediator subunits and their homologues in other eukaryotic cells (http://bio.lundberg.gu.se/medb/).

Fungal Proteins↗
PubMed2006

The classical srb4-138 mutant allele causes dissociation of yeast Mediator.

The Mediator complex is an essential co-activator for RNA polymerase II-dependent transcription in the budding yeast Saccharomyces cerevisiae. The S. cerevisiae core Mediator complex consists of three larger domains that are termed head, middle, and tail. The Med17 subunit is located within the head domain and is essential for cell viability. A temperature-sensitive allele of the MED17 gene known as srb4-138 causes all RNA polymerase II-dependent transcription to cease at the non-permissive temperature. The phenotype of srb4-138 allele has served as the main in vivo proof of the importance of Mediator, but the molecular basis for the effect of this mutant has not been determined. We here characterize Mediator from cells carrying the srb4-138 allele and find that the Mediator complex consistently breaks apart at the head/middle domain boundary even at lower temperatures. We find that both the head and middle domains are able to associate with the RNA polymerase independently of each other. Interestingly, both sub-complexes are able to associate with an active promoter at the permissive temperature but at the non-permissive temperature the head domain is lost from the promoter.

Alleles↗
PubMed2006

Differential enhancement of dengue virus immune complex infectivity mediated by signaling-competent and signaling-incompetent human Fcgamma RIA (CD64) or FcgammaRIIA (CD32).

Fcgamma receptor (FcgammaR)-mediated entry of infectious dengue virus immune complexes into monocytes/macrophages is hypothesized to be a key event in the pathogenesis of complicated dengue fever. FcgammaRIA (CD64) and FcgammaRIIA (CD32), which predominate on the surface of such dengue virus-permissive cells, were compared for their influence on the infectivity of dengue 2 virus immune complexes formed with human dengue virus antibodies. A signaling immunoreceptor tyrosine-based activation motif (ITAM) incorporated into the accessory gamma-chain subunit that associates with FcgammaRIA and constitutively in FcgammaRIIA is required for phagocytosis mediated by these receptors. To determine whether FcgammaRIA and FcgammaRIIA activation functions are also required for internalization of infectious dengue virus immune complexes, we generated native and signaling-incompetent versions of each receptor by site-directed mutagenesis of ITAM tyrosine residues. Plasmids designed to express these receptors were transfected into COS-7 cells, and dengue virus replication was measured by plaque assay and flow cytometry. We found that both receptors mediated enhanced dengue virus immune complex infectivity but that FcgammaRIIA appeared to do so far more effectively. Abrogation of FcgammaRIA signaling competency, either by expression without gamma-chain or by coexpression with gamma-chain mutants, was associated with significant impairment of phagocytosis and of dengue virus immune complex infectivity. Abrogation of FcgammaRIIA signaling competency was also associated with equally impaired phagocytosis but had no discernible effect on dengue virus immune complex infectivity. These findings point to fundamental differences between FcgammaRIA and FcgammaRIIA with respect to their immune-enhancing capabilities and suggest that different mechanisms of dengue virus immune complex internalization may operate between these FcgammaRs.

Animals↗
PubMed2005

Occupancy of the Drosophila hsp70 promoter by a subset of basal transcription factors diminishes upon transcriptional activation.

The presence of general transcription factors and other coactivators at the Drosophila hsp70 gene promoter in vivo has been examined by polytene chromosome immunofluorescence and chromatin immunoprecipitation at endogenous heat-shock loci or at a hsp70 promoter-containing transgene. These studies indicate that the hsp70 promoter is already occupied by TATA-binding protein (TBP) and several TBP-associated factors (TAFs), TFIIB, TFIIF (RAP30), TFIIH (XPB), TBP-free/TAF-containg complex (GCN5 and TRRAP), and the Mediator complex subunit 13 before heat shock. After heat shock, there is a significant recruitment of the heat-shock transcription factor, RNA polymerase II, XPD, GCN5, TRRAP, or Mediator complex 13 to the hsp70 promoter. Surprisingly, upon heat shock, there is a marked diminution in the occupancy of TBP, six different TAFs, TFIIB, and TFIIF, whereas there is no change in the occupancy of these factors at ecdysone-induced loci under the same conditions. Hence, these findings reveal a distinct mechanism of transcriptional induction at the hsp70 promoters, and further indicate that the apparent promoter occupancy of the general transcriptional factors does not necessarily reflect the transcriptional state of a gene.

Animals↗
PubMed1998

In vivo inflammatory response to a prototypic B cell superantigen: elicitation of an Arthus reaction by staphylococcal protein A.

Staphylococcal protein A (SpA) is representative of a new class of Ags, the B cell superantigens (SAgs). These SAgs, unlike conventional Ags, bind to the Fab regions of Ig molecules outside their complementarity-determining regions. In addition, B cell SAgs can react with a substantial amount of a host's serum Igs by virtue of their ability to interact with many members of an entire variable heavy chain (VH) or variable light chain gene family. For example, SpA reacts with the Fabs of most human Igs using heavy chains from the VH3 gene family (VH3+). Members of this gene family are expressed on 30 to 60% of human peripheral B cells. We sought to determine whether the interaction of a B cell SAg with its reactive Igs can elicit immune complex-mediated tissue injury. Using the Arthus reaction in rabbits as an in vivo model of immune complex-mediated tissue inflammation, we demonstrated that untreated rabbits, which were administered SpA intradermally (i.d.), do not develop a cutaneous inflammatory response. However, when rabbits were pretreated i.v. with human IgG (hIgG), i.d. injections of SpA induced an inflammatory response with the classical histologic features of an Arthus reaction. To determine whether this Arthus-like response occurred via a B cell superantigenic mechanism, the rabbits were pretreated with VH3-depleted hIgG and then were administered SpA i.d. We found that the induction of a prominent inflammatory response by SpA was dependent upon the presence of VH3+ molecules in the hIgG pretreatment. These results provide compelling evidence that an interaction of the B cell SAg, SpA, with its reactive (VH3+) IgGs leads to an immune complex-mediated inflammatory response in vivo.

Animals↗
PubMed2002

Interactions of glucose oxidase with various metal polypyridine complexes as mediators of glucose oxidation.

The interaction between glucose oxidase (GOx) and a typical metal complex, which is chemically stable in both oxidized and reduced forms, has been investigated by a voltammetric method. The evaluation of an electron-transfer mediator useful for glucose oxidation is discussed from thermodynamic and kinetic points of view, i.e. the redox potentials of various metal complexes and the second-order rate constants for the electron transfer between GOx in reduced form and the metal complexes in oxidized form. No mediation of glucose oxidation by [Co(bpy)(3)](2+) (bpy=2,2'-bipyridine) or [Cu(bpy)(2)](2+) occurred, in spite of their appropriate redox potentials. This was attributed mainly to the lower electron-self-exchange rates of the mediator and the reaction with GOx. All three types of osmium(II) complexes, [Os(PP) (n)](2+) ( n=2 or 3; PP=polypyridine), [OsL(2)(PP)(2)](2+) (L=imidazole and its derivatives), and [OsClL(bpy)(2)](+), acted as excellent electron-transfer mediators for the glucose oxidation. Mixed ligand complexes, [OsL(2)(PP)(2)](2+) and [OsClL(bpy)(2)](+), have been concluded to be more efficient electron-transfer mediators. The electron-transfer rates between the mediator and GOx have been found to be accelerated by intermolecular electrostatic interactions or hydrogen bonds.

Electrochemistry↗
PubMed1990

Mechanism of action of an inhibitor of complement-mediated prevention of immune precipitation.

Glycoprotein 60 (gp60) is a normal plasma protein (mean concentration in normal serum 34 micrograms/ml) that is present in increased levels (mean concentration 97 micrograms/ml) in the sera of patients with rheumatoid arthritis (RA). Purified gp60 binds to IgG but not to IgM, and competitively inhibits the binding of C1q. In fluid-phase studies, purified gp60 was shown to reduce immune complex-mediated complement activation in a dose-dependent manner. The addition of Fab anti-gp60 to normal serum was associated with (i) increased levels of complement-mediated prevention of immune precipitation (PIP); (ii) increased total haemolytic complement activity when EAIgG, but not when EAIgM, were used as targets; and (iii) increased immune complex-mediated complement activation. Thus gp60 appears to regulate immune complex-mediated classical pathway activation. The findings that Fab anti-gp60 (i) only partly restored PIP in RA sera showing reduced PIP levels and (ii) only partly reduced inhibition of PIP by RA sera, show that gp60 is not entirely responsible for these abnormalities.

Antigen-Antibody Complex↗
PubMed2006

TRIM11 binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105) through the ubiquitin-proteasome system.

TRIM11 is a member of the tripartite-motif-containing protein family and is known to destabilize humanin, an inhibitor of Alzheimer-like neuronal insults. In this study, we demonstrate that TRIM11 interacts with activator-recruited cofactor 105-kDa component (ARC105) that mediates chromatin-directed transcription activation and is a key regulatory factor for transforming growth factor beta (TGFbeta) signaling. Co-expression of TRIM11 increased ARC105 degradation but a proteasome inhibitor suppressed this. Co-expression of TRIM11 and ARC105 also increased ubiquitination of ARC105. In addition, TRIM11 suppressed ARC105-mediated transcriptional activation induced with TGFbeta in a reporter assay. These results suggest that TRIM11, with the ubiquitin-proteasome pathway, regulates ARC105 function in TGFbeta signaling.

Animals↗
PubMed1996

Macrophages stimulate cholesteryl ester accumulation in cocultured smooth muscle cells incubated with lipoprotein-proteoglycan complex.

Foam cells of atherosclerotic lesions originate from both macrophages and smooth muscle cells (SMCs). We explored the mechanism by which SMCs may become lipid laden. Confluent bovine aortic SMCs were cocultured with P388D, macrophages, and the cocultures were incubated for various times with low-density lipoprotein (LDL), acetyl-LDL, or lipoprotein-proteoglycan (PG) complex isolated from human atherosclerotic lesions. Macrophages were then removed from the SMCs and the cholesteryl ester (CE) content of the SMCs was quantitated. Lipoprotein-PG complex but not LDL or acetyl-LDL produced a 6-fold to 9-fold stimulation of CE synthesis and a 4.4-fold increase in cellular CE mass in cocultured SMCs relative to control SMCs. In similar studies with human aortic SMC-macrophage cocultures, macrophages stimulated lipoprotein-PG complex-mediated CE synthesis 7-fold to 13-fold and CE mass 7.8-fold in cocultured SMCs compared with SMCs cultured alone. CE synthesis that was mediated by lipoprotein-PG complex was dose dependent and increased linearly with time. Incubation of lipoprotein-PG complex with SMC-macrophage cocultures but not with SMCs or macrophages alone resulted in aggregation of the complex and stimulation of cholesterol esterification in SMCs by the conditioned media containing the aggregated complex. Cytochalasin D, an inhibitor of phagocytosis, inhibited CE synthesis mediated by lipoprotein-PG complex by 73%, whereas polyinosinic acid, an inhibitor of the scavenger receptor, had no effect. Upregulation or downregulation of apolipoprotein B,E receptors did not affect the lipoprotein-PG complex-mediated CE synthesis by cocultured SMCs. Lipoprotein-PG complex did not stimulate CE synthesis in SMCs cocultured with aortic endothelial cells or macrophages cocultured with SMCs. These results indicate that macrophages can stimulate CE synthesis and accumulation in cocultured SMCs when incubated with lipoprotein-PG complexes isolated from atherosclerotic lesions. This could be a potential mechanism for myocyte foam cell formation.

Animals↗
PubMed1995

Histone H4 proximal promoter mediates a complex transcriptional response during differentiation of 3T3L1 adipocytes.

We have investigated the promoter element(s) required by the cell cycle regulated FO108 human histone H4 gene for control of gene expression during adipocyte proliferation and differentiation. Stable 3T3L1 cell lines were established that express fusion genes in which the histone H4 promoter is joined to chloramphenicol acetyltransferase (cat) as a reporter gene. Expression of the H4CAT fusion genes was monitored in proliferating and confluent 3T3L1 preadipocytes and in differentiating 3T3L1 adipocytes. The results indicate that the H4 cell cycle element (CCE), which mediates S phase-specific stimulation of H4 gene transcription, is not required for transcriptional regulation during differentiation. Instead, a minimal H4 promoter (nucleotides -46 to -11) is sufficient to mediate the complex transcriptional response of H4 gene expression observed during the process of adipocyte differentiation of 3T3L1 cells. In addition, the data suggest that down-regulation of histone gene expression during cellular differentiation may be mediated by passive inactivation of the promoter due to loss of positive regulatory factor(s).

3T3 Cells↗
PubMed1978

Immune complex glomerulonephritis mediated by thyroid antigens.

Hypothyroidism, microscopic hematuria, and proteinuria developed in an 11-year-old girl. A renal biopsy specimen showed increased mesangial cells and matrix with focal glomerular basement membrane thickening. Three years later, a pronounced increase in proteinuria was detected. Elevated levels of antibody to thyroid microsomal antigen and thyroglobulin were found in the serum. A renal biopsy specimen showed a pronounced increase in mesangial cells and matrix with generalized glomerular basement membrane thickening. Electron microscopic studies demonstrated granular deposits in the capillary walls and mesangium. Immunofluorescent studies revealed granular deposits of IgG, IgM, and C3, primarily on the glomerular basement membrane. By indirect immunofluorescence, granular glomerular basement membrane and mesangial staining were detected with antibody specific for thyroglobulin and thyroid microsomal antigen. These observations suggest development of immune complex glomerulonephritis mediated by thyroid antigens.

Antigen-Antibody Complex↗
PubMed2003

Rigidity of collagen fibrils controls collagen gel-induced down-regulation of focal adhesion complex proteins mediated by alpha2beta1 integrin.

Previous studies have shown that collagen gel overlay induced selective proteolysis of focal adhesion complex proteins in Madin-Darby canine kidney (MDCK) cells. In this study, we examined whether morphological and biochemical changes were present in cells cultured on collagen gel. We found that focal adhesion complex proteins, including focal adhesion kinase (FAK), talin, paxillin, and p130cas, but not vinculin, were decreased within 1 h when MDCK cells were cultured on collagen gel. Collagen gel-induced selective decrease of focal adhesion proteins was observed in all lines of cells examined, including epithelial, fibroblastic, and cancer cells. Matrigel also induced selective down-regulation of focal adhesion proteins. However, cells cultured on collagen gel- or matrigel-coated dishes did not show any changes of focal adhesion proteins. These data suggest that the physical nature of the gel, i.e. the rigidity, is involved in the expression of focal adhesion proteins. The collagen gel-induced down-regulation of focal adhesion complex proteins was caused by reduction of protein synthesis and activation of proteases such as calpain. Overexpression of a dominant negative mutant of discoidin domain receptor 1 (DDR1) or FAK-related non-kinase (FRNK) did not prevent collagen gel-induced down-regulation of the focal adhesion complex protein, whereas an anti-alpha2beta1 integrin-neutralizing antibody completely blocked it. Taken together, our results indicate that the rigidity of collagen gel controls the expression of focal adhesion complex proteins, which is mediated by alpha2beta1 integrin but not DDR1.

3T3 Cells↗
PubMed1996

Lupus aortitis: a case report and review of the literature.

Systemic lupus erythematosus is a complex immunological and rheumatological disease that has numerous complications. Central to the pathogenesis of systemic lupus erythematosus is immune complex formation and deposition in blood vessels and end organs. This is a case report of an autopsy of a patient with systemic lupus erythematosus, end stage renal disease, peripheral vascular occlusive disease, pancreatitis, and aortitis. The aortitis was found to be immune complex mediated with deposition of IgG, C3, as well as fibrinogen in the wall of the aorta as shown by immunofluorescence. The hypercoagulable state of the patient is discussed with particular emphasis on the role of anticardiolipin antibodies, antiphospholipid antibodies, and anti-beta-2-glycoprotein I in the pathogenesis. This case is unique in that the immune complex mediated aortitis has not been described in the literature over the past 25 years. We recommend that the diagnosis of immune complex mediated aortitis be considered in the differential diagnosis of aortitis, particularly in the background of a patient with systemic lupus erythematosus.

Adult↗
PubMed1999

An activator binding module of yeast RNA polymerase II holoenzyme.

The Mediator complex of Saccharomyces cerevisiae is required for both general and regulated transcription of RNA polymerase II (PolII) and is composed of two stable subcomplexes (Srb4 and Rgr1 subcomplexes). To decipher the function of each Mediator subcomplex and to delineate the functional relationship between the subcomplexes, we characterized the compositions and biochemical activities of PolII-Mediator complexes (holoenzymes) prepared from several Mediator mutant strains of S. cerevisiae. We found that holoenzymes devoid of a functional Gal11 module were defective for activated but not basal transcription in a reconstituted in vitro system. This activation-specific defect was correlated with a crippled physical interaction to transcriptional activator proteins, which could be bypassed by artificial recruitment of a mutant holoenzyme to a promoter. Consistent with this observation, a direct interaction between Gal11 and gene-specific transcriptional activator proteins was detected by far-Western analyses and column binding assays. In contrast, the srb5 deletion mutant holoenzyme was defective for both basal and activated transcription, despite its capacity for activator binding that is comparable to that of the wild-type holoenzyme. These results demonstrate that the Gal11 module of the Rgr1 subcomplex is required for the efficient recruitment of PolII holoenzyme to a promoter via activator-specific interactions, while the Srb4 subcomplex functions in the modulation of general polymerase activity.

DNA-Binding Proteins↗