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At least 703 records · Page 39Linked to original sources
PubMed2004

BRCA1 function mediates a TRAP/DRIP complex through direct interaction with TRAP220.

Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene mutated in a high percentage of hereditary breast and ovarian cancers. The multifunctional BRCA1 protein acts on cell cycle control, exerting several highly specialized DNA repair processes through diverse domains. Gene regulation through its C-terminal domain (BRCT) is indispensable for BRCA1-mediated tumor suppression, suggesting the possibility that the BRCT domain interacts with co-regulator complexes. Using a biochemical approach with HeLa S3 nuclear extracts, we isolated BRCT-associated complexes and identified one of the purified components as TRAP220. We then performed interaction studies in vivo (co-immunoprecipitation) and in vitro (glutathione S-transferase pull-down assays) and showed that BRCT directly interacted with TRAP220. This in vitro interaction was completely abolished by BRCT point mutations typical of those found in patients with BRCA1 that lack transactivation function. BRCA1 transactivation function was dependent on TRAP220 expression level in a transient expression assay. Moreover, a cell survival assay showed that antisense TRAP220 expression to disrupt endogenous TRAP220 expression significantly reduced the survival rate potentiated by BRCA1 after DNA damage. These results suggested that a TRAP220 complex play an important role as putative co-activator complexes in BRCA1-mediated tumor suppression.

BRCA1 Protein↗
PubMed1999

Synergistic transcriptional activation by hGABP and select members of the activation transcription factor/cAMP response element-binding protein family.

The Ets-related DNA-binding protein human GA-binding protein (hGABP) alpha interacts with the four ankyrin-type repeats of hGABPbeta to form an hGABP tetrameric complex that stimulates transcription through the adenovirus early 4 (E4) promoter. Using co-transfection assays, this study demonstrated that the hGABP complex mediated efficient activation of transcription from E4 promoter synergistically with activating transcription factor (ATF) 1 or cAMP response element-binding protein (CREB), but not ATF2/CRE-BP1. This synergy also partially occurred when hGABPalpha was used alone in place of the combination of hGABPalpha and hGABPbeta. hGABP activated an artificial promoter containing only ATF/CREB-binding sites under coexistence of ATF1 or CREB. Consistent with these results, physical interactions of hGABPalpha with ATF1 or CREB were observed in vitro. Functional domain analyses of the physical interactions revealed that the amino-terminal region of hGABPalpha bound to the DNA-binding domain of ATF1, which resulted in the formation of ternary complexes composed of ATF1, hGABPalpha, and hGABPbeta. In contrast to hGABPalpha, hGABPbeta did not significantly interact with ATF1 and CREB. Taken together, these results indicate that hGABP functionally interacts with selective members of the ATF/CREB family, and also suggest that synergy results from multiple interactions which mediate stabilization of large complexes within the regulatory elements of the promoter region, including DNA-binding and non-DNA-binding factors.

Activating Transcription Factor 1↗
PubMed1992

Attempts to induce immune-mediated cerebral arterial injury for an experimental model of moyamoya disease.

To examine the possible role of immune complex-mediated reactions in moyamoya disease, a novel experimental system using a serum sickness vasculitis model combined with intracisternal administration of antibodies or antigens was developed. Twenty-eight male Japanese white rabbits were divided into four experimental groups. Group I was treated twice with intravenous injections of heterologous serum. In group II, intracisternal administration of antibodies or antigens was combined with the second injection of serum. Group III received a single intravenous injection of antigens simultaneously with intracisternal administration of antibodies. Group IV was a technical control group. Cerebral arteritis, although likely in the initial process, was induced only in groups II and III. This study suggests that the cerebral arteries rarely develop arteritis in a serum sickness model alone. The cerebral arteries may require additional intracisternal administration of antibodies or antigens to induce in situ deposition of immune complexes around them.

Animals↗
PubMed1996

Mercury induces polyclonal B cell activation, autoantibody production and renal immune complex deposits in young (NZB x NZW)F1 hybrids.

It is well established that in susceptible mouse strains, chronic treatment with subtoxic doses of mercuric chloride (HgCl2) induces a systemic autoimmune disease, which is characterized by increased serum levels of IgG1 and IgE antibodies, by the production of anti-nucleolar antibodies and by the development of immune complex-mediated glomerulonephritis. Susceptibility to mercury is partly under the control of major histocompatibility complex genes. To study the susceptibility to mercury further, we investigated the in vivo effects of mercury in young autoimmune disease prone (NZB x NZW)F1 (H-2d/z) mice prior to establishment of spontaneous autoimmune disease. Mercury-susceptible SJL (H-2s) mice and mercury low-responder BALB/c (H-2d) mice were used as positive and negative controls, respectively. In (NZB x NZW)F1 mice, treatment with mercury stimulated an intense antibody formation characterized by increased numbers of splenic IgG1 and IgG3 antibody-producing cells as well as by elevated serum IgE levels. Injection with mercury also induced an increased production of IgG1, IgG2b and IgE antibodies in SJL, but not in BALB/c mice. The mercury-induced IgG1 response in (NZB x NZW)F1 and SJL mice was found to be polyclonal and autoantibodies against double-stranded (ds)DNA, IgG, collagen, cardiolipin, phosphatidylethanolamine as well as antibodies against the hapten trinitrophenol were produced. In addition, SJL, but not (NZB x NZW)F1 or BALB/c mice, produced IgG1 anti-nucleolar antibodies after treatment with mercury. Further studies demonstrated that (NZB x NZW)F1 and SJL mice developed high titers of renal mesangial immune complex deposits containing IgG1 antibodies 3 weeks after injection with mercury. Thus, a mouse strain genetically prone to develop spontaneous autoimmune diseases is highly susceptible to mercury-induced immunopathological alterations.

Animals↗
PubMed1996

Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death.

Through its type 1 receptor (TNFR1), the cytokine TNF elicits an unusually wide range of biological responses, including inflammation, tumor necrosis, cell proliferation, differentiation, and apoptosis. We investigated how TNFR1 activates different effector functions; the protein kinase JNK, transcription factor NF-kappaB, and apoptosis. We found that the three responses are mediated through separate pathways. Recruitment of the signal transducer FADD to the TNFR1 complex mediates apoptosis but not NF-kappaB or JNK activation. Two other signal transducers, RIP and TRAF2, mediate both JNK and NF-kappaB activation. These two responses, however, diverge downstream to TRAF2. Most importantly, JNK activation is not involved in induction of apoptosis, while activation of NF-kappaB protects against TNF-induced apoptosis.

Adenocarcinoma↗
PubMed1992

Double-stranded RNA and interferon-alpha induce transcription through different molecular mechanisms.

Double-stranded (ds) RNA stimulates the synthesis of several mRNAs known to be induced by type I interferons (IFNs). In this report, it is shown that the IFN-alpha stimulated genes (ISGs) 15, 54, 56, and GBP are transcriptionally induced by dsRNA. Transcriptional stimulation occurred in the presence of the protein synthesis inhibitor cycloheximide (CHX), indicating that inducibility was directly mediated by dsRNA through the action of preformed proteins. ISGF-3, the protein complex mediating primary transcriptional induction of ISGs by IFN-alpha, was not activated by dsRNA in the presence of CHX. Additionally, DNA-binding activity of ISGF-2/IRF-1, a protein involved in the regulation of the IFN-beta gene and ISGs, did not correlate with dsRNA-induced transcriptional induction of ISGs. This suggests that dsRNA and IFN-alpha induce ISGs through different molecular mechanisms.

Cycloheximide↗
PubMed1993

Combinations of low concentrations of cytokines and acute agonists synergize in increasing the permeability of endothelial monolayers.

The deposition of circulating immune reactants in blood vessels, an important event in the pathogenesis of certain types of vasculitis, requires an increase in permeability in the endothelial monolayer. An in vitro model to examine the integrity of endothelial cell monolayers and their response to inflammatory mediators has been developed. Human umbilical vein endothelial cells were grown to confluence on an FITC-labelled matrix and monolayer integrity was assessed by the exclusion of a 125I-anti-FITC antibody. Alteration in endothelial monolayer permeability was associated with an increase in uptake of 125I-anti-FITC antibody, expressed as a percentage of the maximal uptake of antibody on to FITC-matrix from which endothelial cells had been stripped. We determined the effects on endothelial monolayer permeability of acute agonists (thrombin and histamine), cytokines (tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-1 and IL-4) and combinations of acute agonists and cytokines. Addition of thrombin in concentrations ranging from 0.5 to 15 U/ml led to an increased uptake of 125I-anti-FITC antibody from 2% to 15% relative to unstimulated endothelium. For other agonists and cytokines the increases in permeability were: (i) histamine (50-400 pmol/ml) increased uptake 5-22%; (ii) TNF (12.5-100 ng/ml) increased uptake 2-12%; (iii) IFN-gamma (125-250 U/ml) increased uptake 1.5-3%. IL-1 beta (50-100 U/ml) and IL-4 (50-100 U/ml) had no effect. Synergistic interactions on endothelial monolayer permeability were seen with the following combinations: (i) IL-4 (100 U/ml) and TNF (12.5 ng/ml) uptake 11%; (ii) IL-4 (100 U/ml) and IFN-gamma (125 U/ml) uptake 6.5%; (iii) TNF (12.5 ng/ml) and IFN-gamma (125 ng/ml) uptake 7%; (iv) thrombin (0.5 U/ml) and histamine (50 pmol/ml) uptake 13.5%; and (v) TNF (12.5 ng/ml) and thrombin (0.5 U/ml) uptake 8.5%. These observations suggest that interactions between cytokines and acute inflammatory mediators such as thrombin and histamine may be important in determining whether immune complexes are deposited in vessel walls. This model system may now be useful for the further investigation in vitro of the mechanisms involved in the pathogenesis of immune complex-mediated vascular damage.

Animals↗
PubMedDate not supplied

CD4/CD8 lymphocytes in BALF during the efferent phase of lung delayed-type hypersensitivity reaction induced by single antigen inhalation.

BACKGROUND: The precise mechanisms involved in the pathogenesis of hypersensitivity pneumonitis (HP) have not been identified. HP is characterized by inflammatory lymphocytic alveolitis and a remarkable increase in T-lymphocytes detected in bronchoalveolar lavage fluid (BALF). It is suggested that both CD4+ and CD8+ T cells may contribute to the pathogenesis of HP. Experiments on animal models suggest that cell mediated immunity (CMI) is more important for the pathogenesis of HP than complex-mediated immunity, but the relationship between the subsets of BALF lymphocytes and humoral or cell-mediated allergic reactions is still not clear. The aim of our study was distinguish CD4+ and CD8+ T cells in BALF lymphocytes during a delayed-type hypersensitivity (DTH) reaction in the lung. MATERIAL AND METHODS: The experiment was performed on guinea pigs sensitized with BCG vaccine and subjected to a single inhalation of tubercle bacilli antigens (tuberculin). 24 hours after tuberculin provocation (at the time of maximum lymphocyte infiltration), bronchoalveolar lavage was performed on both sensitized and non-sensitized (control) animals. The total cell count was estimated, and a differential microscopical examination of BAL-fluid cells was performed, along with the phenotyping of BALF lymphocytes (by flow cytometry). RESULTS: In the BALF of the sensitized animals, as compared to the controls, there was a statistically significant increase in the percentage and absolute count of T-lymphocytes, CD4+ and CD8+. The CD4 / CD8 ratio in both groups did not differ significantly and was individually variable (2.94I0.72 SEM in the experimental group, vs 4.41I1.29 SEM in the control group). CONCLUSIONS: Both CD4+ and CD8+ lymphocytes (with some predominance of helper cells) participate in the efferent phase of the delayed type hypersensitivity reaction in the lung induced by antigen inhalation.

Animals↗
PubMed1985

[Elimination of immune complexes: role of complement].

For many years it has been considered that complement does not modify the immune elimination of antigen-antibody complexes. However, recent studies suggest that complement contributes to the normal processing of immune complexes: (1) complement activation modifies the structure of the immune complex lattice and produces soluble complexes, (2) erythrocytes bind complement reacted complexes and deliver them to the fixed macrophage system. The clinical association between inherited complement deficiency and immune complex mediated diseases also suggests a role for complement in the physiological elimination of complexes.

Antigen-Antibody Complex↗
PubMed1994

Protoporphyrin IX, an endogenous ligand of the peripheral benzodiazepine receptor, potentiates induction of the mitochondrial permeability transition and the killing of cultured hepatocytes by rotenone.

The peripheral benzodiazepine receptor (PBzR) is associated with the outer mitochondrial membrane. Protoporphyrin IX (PPIX), an endogenous substance with high affinity for the PBzR, induced the inner membrane permeability transition (MPT) in respiring liver mitochondria de-energized by carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Cyclosporin A (CyA), an inhibitor of the permeability transition, prevented this effect. In cultured hepatocytes, the MPT was measured as an increased [3H]sucrose-accessible space sensitive to CyA. Nanomolar concentrations of PPIX potentiated the induction of the MPT and the extent of cell killing in hepatocyte cultures de-energized by rotenone. CyA prevented the enhanced cell killing by PPIX. PPIX did not increase the rate or extent of ATP depletion, the loss of the mitochondrial membrane potential, or the accumulation of long chain acyl-CoA thioesters. The association of the PBzR with the voltage-dependent anion channel of the outer mitochondrial membrane and with the adenine nucleotide carrier of the inner membrane suggests that this complex mediates the transport of PPIX across the mitochondrial membranes. In turn, this same complex participates in the MPT. Thus, the same structural complex (PBzR, voltage-dependent anion channel, and adenine nucleotide carrier) can interact with the endogenous substrate PPIX to result in different functional consequences depending on the state of mitochondrial energization.

Adenosine Triphosphate↗
PubMed2005

PIKE/nuclear PI 3-kinase signaling in preventing programmed cell death.

PI 3-kinase enhancer (PIKE) is a nuclear GTPase that enhances PI 3-kinase (PI3K) activity. Nerve growth factor (NGF) treatment leads to PIKE activation by triggering the nuclear translocation of PLC-gamma1, which acts as a physiological guanine nucleotide exchange factor (GEF) for PIKE. PI3K occurs in the nuclei of a broad range of cell types, and various stimuli elicit PI3K nuclear translocation. While cytoplasmic PI3K has been well characterized, little is known about the biological function of nuclear PI3K. Surprisingly, nuclei from 30 min NGF-treated PC12 cells are resistant to DNA fragmentation initiated by the activated cell-free apoptosome, and both PIKE and nuclear PI3K are sufficient and necessary for this effect. Moreover, pretreatment of the control nucleus with PI(3,4,5)P3 alone mimics the anti-apoptotic activity of NGF by selectively preventing apoptosis, for which nuclear Akt is required but not sufficient. Recently, a nuclear PI(3,4,5)P3 receptor, nucleophosmin/B23, has been identified from NGF-treated PC12 nuclear extract. PI(3,4,5)P3/B23 complex mediates the anti-apoptotic effects of NGF by inhibiting DNA fragmentation activity of caspase-activated DNase (CAD). Thus, PI(3,4,5)P3/B23 complex and nuclear Akt effectors might coordinately mediate PIKE/nuclear PI3K signaling in promoting cell survival by NGF.

Animals↗
PubMed2005

Common mechanisms in immune-mediated inflammatory disease.

Characterization of the K/BxN mouse model of spontaneous arthritis contributed to the rediscovery of immune complex-mediated inflammation in rheumatoid arthritis (RA). Serum from these animals can transfer joint-specific inflammation to normal mice. Fc receptors, interleukin 1, mast cells, and complement are all essential for the development of arthritis after serum transfer. In RA, additional amplifying factors have been identified, including cytokines and intracellular signaling molecules, such as mitogen-activated protein kinases and nuclear factor kappa B, that perpetuate inflammation. Understanding the autoimmune and inflammatory pathways implicated in disease has led to targeted drug development and improved clinical outcomes.

Animals↗
PubMed2006

The pathogenetic aspects and gene polymorphisms of IgA nephropathy.

Immunoglobulin A nephropathy is an immune-complex-mediated glomerulonephritis characterized by diffuse mesangial deposition of immunoglobulin A or IgA--containing immune complexes. Although its most common clinical presentation is macroscopic hematuria provoked by upper respiratory tract infection, this is neither universal nor necessary for the diagnosis. The patients with IgA nephropathy manifest with variable clinical symptoms (e.g., microhematuria with preserved renal function or progressive deterioration of renal functions resulting in end-stage renal disease). The pathogenetic mechanisms include the abnormality of O-glycosylation of the IgA1 molecule, genetic factors, environmental factors and various inflammatory mediators. The source of mesangial IgA deposits is total circulating serum IgA but the response of the mesangium and the mesangial cells to the deposited IgA is critical to the development of IgAN. Without a genetic predisposition to IgAN, IgA deposition can cause no risk for triggering glomerulonephritis. If generic progression risk factors of an unfavourable outcome coincide (e.g. hypertension, severe proteinuria, elevated serum creatinine level), this will increase the likelihood of progressive renal impairment. Further studies are needed to disclose the precise pathogenetic mechanisms involved in primary IgA nephropathy and to facilitate the development of newer therapeutic possibilities.

Glomerulonephritis, IGA↗
PubMed1976

The glomerular complement receptor in immunologically mediated renal glomerular injury.

We examined 25 renal-biopsy specimens to determine whether there is a relation between immunologically mediated renal diseases and the activity of complement receptors that selectively bind antigen-antibody complexes containing activated third component of complement (C3b). These receptors have been termed glomerular complement receptors. Renal lesions associated with in vivo deposition were associated with a loss of receptor sites as demonstrated by reduced or absent in vitro binding of C3b-coated test reagents by glomerular complement receptor. These findings suggest that binding of complement containing immune complexes to glomerular complement receptors in human subjects may participate in the immunopathologic processes of certain immune-complex-mediated renal diseases.

Antibody Specificity↗
PubMed2000

Mediator of transcriptional regulation.

Three lines of evidence have converged on a multiprotein Mediator complex as a conserved interface between gene-specific regulatory proteins and the general transcription apparatus of eukaryotes. Mediator was discovered as an activity required for transcriptional activation in a reconstituted system from yeast. Upon resolution to homogeneity, the activity proved to reside in a 20-protein complex, which could exist in a free state or in a complex with RNA polymerase II, termed holoenzyme. A second line of evidence came from screens in yeast for mutations affecting transcription. Two-thirds of Mediator subunits are encoded by genes revealed by these screens. Five of the genetically defined subunits, termed Srbs, were characterized as interacting with the C-terminal domain of RNA polymerase II in vivo, and were shown to bind polymerase in vitro. A third line of evidence has come recently from studies in mammalian transcription systems. Mammalian counterparts of yeast Mediator were shown to interact with transcriptional activator proteins and to play an essential role in transcriptional regulation. Mediator evidently integrates and transduces positive and negative regulatory information from enhancers and operators to promoters. It functions directly through RNA polymerase II, modulating its activity in promoter-dependent transcription. Details of the Mediator mechanism remain obscure. Additional outstanding questions include the patterns of promoter-specificity of the various Mediator subunits, the possible cell-type-specificity of Mediator subunit composition, and the full structures of both free Mediator and RNA polymerase II holoenzyme.

Animals↗
PubMed2005

Regulation of cortactin/dynamin interaction by actin polymerization during the fission of clathrin-coated pits.

Separation of clathrin-coated pits from the plasma membrane, a key event during endocytosis, is thought to be driven by dynamin and the actin cytoskeleton. However, the mechanism for the actin-mediated endocytosis remains elusive. RNA interference-mediated suppression of cortactin, an F-actin binding protein that promotes Arp2/3 complex-mediated actin polymerization, effectively blocked transferrin uptake. Depletion of cortactin in brain cytosol inhibited formation of clathrin-coated vesicles by 70% as analyzed in a cell-free system. Interestingly, the interaction between cortactin and dynamin 2 in cells was dependent on actin polymerization and was attenuated upon cell exposure to cytochalasin D as analyzed by immunofluorescence and immunoprecipitation. Moreover, a cortactin mutant deficient in Arp2/3 binding colocalized less efficiently with dynamin 2 and inhibited the uptake of transferrin. The effect of actin polymerization on the interaction between cortactin and the dynamin proline-rich domain (PRD) was further evaluated under a condition for actin polymerization in vitro. Cortactin binds to the dynamin PRD with an equilibrium dissociation constant of 81 nM in the presence of the Arp2/3 complex and actin, and 617 nM in the absence of actin polymerization. Taken together, these data demonstrate that Arp2/3-mediated actin polymerization regulates the accessibility of cortactin to dynamin 2 and imply a novel mechanism by which cortactin and dynamin drive the fission of clathrin-coated pits in an actin polymerization dependent manner.

Actin Cytoskeleton↗
PubMed1982

Pathomechanisms of dextran-induced anaphylactoid/anaphylactic reactions in man.

Immune complex-mediated (type III) anaphylaxis is shown to be the pathomechanism of severe dextran-induced anaphylactic reactions in man. Mild reactions may be either antibody-dependent or not. Patients with severe reactions have regularly high titers of preformed, circulating dextran-reactive antibodies and represent a small subpopulation of high responders to dextran. Upon infusion of clinical dextran, noxious immune complexes are formed, leading to mediator release and symptoms of anaphylaxis. Consequently, application of the hapten inhibition principle is recommended for prevention of such reactions.

Anaphylaxis↗
PubMed2006

Lipid mediator informatics-lipidomics: novel pathways in mapping resolution.

Lipidomics, the systematic decoding of lipid-based information in biosystems, is composed of identifying and profiling lipids and lipid-derived mediators. As currently practiced, lipidomics can be subdivided into architecture/membrane lipidomics and mediator lipidomics. The mapping of structural components and their relation to cell activation as well as generation of potent lipid mediators and networks involves a mass spectrometry-computational approach so that interrelationships and complex mediator networks important for cell homeostasis can be appreciated. Cell membranes are composed of a bilayer that contains phospholipids, fatty acids, integral membrane proteins, membrane-associated proteins, sphingolipids, and so on. The membrane composition of many cell types has been established. The components' organization and effect on cell function remains to be established, however, and is a quest for lipidomics. Here, we review liquid chromatography tandem mass spectrometry-based lipidomic analyses to address bioactive lipid mediators in signaling pathways and the roles of lipid-derived mediators in resolution of inflammation.

Animals↗