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At least 559 records · Page 31Linked to original sources
PubMed1985

Septal driving of hippocampal theta rhythm: role of gamma-aminobutyrate-benzodiazepine receptor complex in mediating effects of anxiolytics.

In free-moving male rats, when the hippocampal theta rhythm is artificially driven by stimulation in the septum at frequencies between 5 and 10 Hz, the function relating frequency to the threshold current required to drive the theta rhythm has a minimum at 7.7 Hz. This minimum is eliminated by anxiolytic drugs. Dose-response curves for this effect are reported for chlordiazepoxide, diazepam and meprobamate. The effect of meprobamate was reversed by two gamma-aminobutyrateA antagonists, picrotoxin and bicuculline, which have previously been shown to be without effects of their own. The gamma-aminobutyrateB agonist, baclofen, also without effect on its own, blocked the elimination of the 7.7-Hz minimum caused by the gamma-aminobutyrateA agonist, muscimol. The beta-carboline, ethyl-beta-carboline-3-carboxylate, had mixed agonist/antagonist properties, blocking the effects of chlordiazepoxide, diazepam and muscimol (though not sodium amylobarbitone) but itself acting like a benzodiazepine. Coupled with earlier data, these findings support a role for gamma-aminobutyrate receptors in mediating the effects of anxiolytic drugs.

Animals↗
PubMed2004

Crystallization and preliminary X-ray diffraction studies of the metal-ion-mediated ternary complex of the HutP protein with L-histidine and its cognate RNA.

HutP is an RNA-binding protein that regulates the expression of the Bacillus subtilis hut operon by binding to cis-acting regulatory sequences within hut mRNA, exclusively in the presence of L-histidine. We recently solved the crystal structure of a binary complex (HutP with an L-histidine analog) that revealed a novel RNA-binding fold, and identified the important residues that interact with the L-histidine analog. In addition, we have defined the minimal RNA binding segment that is required for HutP recognition. Interestingly, we showed that ternary complex formation depends on the availability of not only L-histidine but also divalent metal ions. Here we report the crystallization and preliminary X-ray diffraction analysis of the HutP ternary complex. The ternary complex was crystallized in the presence of Mg2+ along with L-histidine and hut mRNA, using the hanging drop vapor diffusion method. The crystal belongs to the R3 space group, with unit cell parameters a=b=75.30 A, c=133.8 A. A complete data set at 1.60 A was collected.

Bacillus subtilis↗
PubMed1985

Copper(I)-bleomycin: structurally unique complex that mediates oxidative DNA strand scission.

Copper(I)-bleomycin [Cu(I) X BLM] was characterized in detail by 13C and 1H NMR. Unequivocal chemical shift assignments for Cu(I) X BLM and Cu(I) X BLM X CO were made by two-dimensional 1H-13C correlated spectroscopy and by utilizing the observation that Cu(I) X BLM was in rapid equilibrium with Cu(I) and metal-free bleomycin, such that individual resonances in the spectra of BLM and Cu(I) X BLM could be correlated. The binding of Cu(I) by bleomycin involves the beta-aminoalaninamide and pyrimidinyl moieties, and possibly the imidazole, but not N alpha of beta-hydroxyhistidine. Although no DNA strand scission by Cu(II) X BLM could be demonstrated in the absence of dithiothreitol, in the presence of this reducing agent substantial degradation of [3H]DNA was observed, as was strand scission of cccDNA. DNA degradation by Cu(I) X BLM was shown not to depend on contaminating Fe(II) and not to result in the formation of thymine propenal; the probable reason(s) for the lack of observed DNA degradation in earlier studies employing Cu(II) X BLM and dithiothreitol was (were) also identified. DNA strand scission was also noted under anaerobic conditions when Cu(II) X BLM and iodosobenzene were employed. If it is assumed that the mechanism of DNA degradation in this case is the same as that under aerobic conditions (i.e., with Cu(I) X BLM + O2 in the presence of dithiothreitol), then Cu X BLM must be capable of functioning as a monooxygenase in its degradation of DNA.

Bleomycin↗
PubMed2002

A component of the ARC/Mediator complex required for TGF beta/Nodal signalling.

The transforming growth factor beta (TGF beta) family of cytokines, including Nodal, Activin and bone morphogenetic protein (BMP), have essential roles in development and tumorigenesis. TGF beta molecules activate the Smad family of signal transducers, which form complexes with specific DNA-binding proteins to regulate gene expression. Two discrete Smad-dependent signalling pathways have been identified: TGF beta, Activin and Nodal signal via the Smad2 (or Smad3)-Smad4 complex, whereas BMP signals via the Smad1-Smad4 complex. How distinct Smad complexes regulate specific gene expression is not fully understood. Here we show that ARC105, a component of the activator-recruited co-factor (ARC) complex or the metazoan Mediator complex, is essential for TGF beta/Activin/Nodal/Smad2/3 signal transduction. Expression of ARC105 stimulates Activin/Nodal/Smad2 signalling in Xenopus laevis embryos, inducing axis duplication and mesendoderm differentiation, and enhances TGF beta response in human cells. Depletion of ARC105 inhibits TGF beta/Activin/Nodal/Smad2/3 signalling and Xenopus axis formation, but not BMP/Smad1 signalling. ARC105 protein binds to Smad2/3-Smad4 in response to TGF beta and is recruited to Activin/Nodal-responsive promoters in chromatin in a Smad2-dependent fashion. Thus ARC105 is a specific and key ARC/Mediator component linking TGF beta/Activin/Nodal/Smad2/3 signalling to transcriptional activation.

Activins↗
PubMed2003

Regulation of transcription by the heterogeneous nuclear ribonucleoprotein E1B-AP5 is mediated by complex formation with the novel bromodomain-containing protein BRD7.

E1B-AP5 was initially identified as a target of the early adenovirus E1B-55 kDa protein during the course of lytic infection. E1B-AP5 belongs to the heterogeneous nuclear ribonucleoprotein family and was demonstrated to be involved in mRNA processing and transport [Gabler, Schutt, Groitl, Wolf, Shenk and Dobner (1998) J. Virol. 72, 7960-7971]. In the present paper, we demonstrate that E1B-AP5 differentially regulates basic and ligand-dependent transcription. We found that E1B-AP5 represses basic transcription driven by several virus and cellular promoters, and mapped the repression activity to the N-terminal part of the protein. In contrast with basic repression, E1B-AP5 activated the glucocorticoid-dependent promoter in the absence of dexamethasone, but did not contribute to the dexamethasone-induced activation. Mutant analysis indicated the presence of an additional cellular factor that modulates E1B-AP5 transcriptional activity. Using yeast two-hybrid screening, we identified a novel chromatin-associated bromodomain-containing protein, BRD7, as an E1B-AP5 interaction partner. We confirmed E1B-AP5-BRD7 complex formation in vivo and in vitro. We found that, although BRD7 binds to histones H2A, H2B, H3 and H4 through its bromodomain, this domain was not necessary for the interaction with E1B-AP5. Indeed, the triple complex formation of E1B-AP5, BRD7 and histones was demonstrated. Disruption of the E1B-AP5-BRD7 complex increased E1B-AP5 repression activity for basic transcription and converted it from being an activator of the hormone-dependent promoter into being a strong repressor. We conclude that complex formation between BRD7 and E1B-AP5 links chromatin events with mRNA processing at the level of transcriptional regulation.

Animals↗
PubMed1999

Cloning and expression of a b(0,+)-like amino acid transporter functioning as a heterodimer with 4F2hc instead of rBAT. A new candidate gene for cystinuria.

We have cloned a transporter protein from rabbit small intestine, which, when coexpressed with the 4F2 heavy chain (4F2hc) in mammalian cells, induces a b(0,+)-like amino acid transport activity. This protein (4F2-lc6 for the sixth member of the 4F2 light chain family) consists of 487 amino acids and has 12 putative transmembrane domains. At the level of amino acid sequence, 4F2-lc6 shows significant homology (44% identity) to the other five known members of the 4F2 light chain family, namely LAT1 (4F2-lc1), y(+)LAT1 (4F2-lc2), y(+)LAT2 (4F2-lc3), xCT (4F2-lc4), and LAT2 (4F2-lc5). The 4F2hc/4F2-lc6 complex-mediated transport process is Na(+)-independent and exhibits high affinity for neutral and cationic amino acids and cystine. These characteristics are similar to those of the b(0,+)-like amino acid transport activity previously shown to be associated with rBAT (protein related to b(0,+) amino acid transport system). However, the newly cloned 4F2-lc6 does not interact with rBAT. This is the first report of the existence of a b(0,+)-like amino acid transport process that is independent of rBAT. 4F2-lc6 is expressed predominantly in the small intestine and kidney. Based on the characteristics of the transport process mediated by the 4F2hc/4F2-lc6 complex and the expression pattern of 4F2-lc6 in mammalian tissues, we suggest that 4F2-lc6 is a new candidate gene for cystinuria.

Alanine↗
PubMed2001

Ligand-dependent formation of retinoid receptors, receptor-interacting protein 140 (RIP140), and histone deacetylase complex is mediated by a novel receptor-interacting motif of RIP140.

Receptor-interacting protein 140 (RIP140) interacts with retinoic acid receptor and retinoid X receptor in a ligand-dependent manner and suppresses retinoic acid (RA) induction of its target genes. The receptor-interacting motif is mapped to a C-terminal peptide sequence (LTKTNPILYYMLQK) of RIP140. The functional role of this motif in mediating the suppressive effects of RIP140 on RA induction is demonstrated in mutation studies. RA induces coimmunoprecipitation of histone deacetylase 3 with retinoic acid receptor/retinoid X receptor in the presence of wild type RIP140, but not in the presence of the C-terminal motif-deleted RIP140. A decrease in histone acetylation on the promoter region that carries a RA response element is associated with the expression of wild type RIP140, but not with expression of the mutant RIP140, in a dose-dependent manner. These data provide a molecular explanation for RIP140 acting as a novel ligand-dependent, negative modulator of RA-regulated gene expression.

Acetylation↗
PubMed2002

Sequential SNARE disassembly and GATE-16-GOS-28 complex assembly mediated by distinct NSF activities drives Golgi membrane fusion.

Characterization of mammalian NSF (G274E) and Drosophila NSF (comatose) mutants revealed an evolutionarily conserved NSF activity distinct from ATPase-dependent SNARE disassembly that was essential for Golgi membrane fusion. Analysis of mammalian NSF function during cell-free assembly of Golgi cisternae from mitotic Golgi fragments revealed that NSF disassembles Golgi SNAREs during mitotic Golgi fragmentation. A subsequent ATPase-independent NSF activity restricted to the reassembly phase is essential for membrane fusion. NSF/alpha-SNAP catalyze the binding of GATE-16 to GOS-28, a Golgi v-SNARE, in a manner that requires ATP but not ATP hydrolysis. GATE-16 is essential for NSF-driven Golgi reassembly and precludes GOS-28 from binding to its cognate t-SNARE, syntaxin-5. We suggest that this occurs at the inception of Golgi reassembly to protect the v-SNARE and regulate SNARE function.

Adenosine Triphosphatases↗
PubMed2003

The intramitochondrial dynamin-related GTPase, Mgm1p, is a component of a protein complex that mediates mitochondrial fusion.

A balance between fission and fusion events determines the morphology of mitochondria. In yeast, mitochondrial fission is regulated by the outer membrane-associated dynamin-related GTPase, Dnm1p. Mitochondrial fusion requires two integral outer membrane components, Fzo1p and Ugo1p. Interestingly, mutations in a second mitochondrial-associated dynamin-related GTPase, Mgm1p, produce similar phenotypes to fzo1 and ugo cells. Specifically, mutations in MGM1 cause mitochondrial fragmentation and a loss of mitochondrial DNA that are suppressed by abolishing DNM1-dependent fission. In contrast to fzo1ts mutants, blocking DNM1-dependent fission restores mitochondrial fusion in mgm1ts cells during mating. Here we show that blocking DNM1-dependent fission in Deltamgm1 cells fails to restore mitochondrial fusion during mating. To examine the role of Mgm1p in mitochondrial fusion, we looked for molecular interactions with known fusion components. Immunoprecipitation experiments revealed that Mgm1p is associated with both Ugo1p and Fzo1p in mitochondria, and that Ugo1p and Fzo1p also are associated with each other. In addition, genetic analysis of specific mgm1 alleles indicates that Mgm1p's GTPase and GTPase effector domains are required for its ability to promote mitochondrial fusion and that Mgm1p self-interacts, suggesting that it functions in fusion as a self-assembling GTPase. Mgm1p's localization within mitochondria has been controversial. Using protease protection and immuno-EM, we have shown previously that Mgm1p localizes to the intermembrane space, associated with the inner membrane. To further test our conclusions, we have used a novel method using the tobacco etch virus protease and confirm that Mgm1p is present in the intermembrane space compartment in vivo. Taken together, these data suggest a model where Mgm1p functions in fusion to remodel the inner membrane and to connect the inner membrane to the outer membrane via its interactions with Ugo1p and Fzo1p, thereby helping to coordinate the behavior of the four mitochondrial membranes during fusion.

Dynamins↗
PubMed1981

The spectrum of inflammatory skin disease following jejuno-ileal bypass for morbid obesity.

From a series of 105 patients who had undergone jejuno-ileal bypass for morbid obesity, seven developed an episodic illness featuring inflammatory skin lesions, usually associated with a non-destructive polyarthritis. Tenosynovitis, myalgia and fever had also occurred. The illness abated spontaneously in four patients. The most characteristic skin lesion was an erythematous macule which developed a central vesicle or pustule. Erythema nodosum-like lesions and liquefying nodules were also seen. Early lesions were characterised by a dense accumulation of neutrophils. Changes is dermal vessels were less destructive than is usually seen in immune complex mediated vasculitis. Circulating immune complexes could be demonstrated in patients actively developing skin lesions. They were also found in some patients long after activity had ceased and in jejuno-ileal bypass subjects who had never developed inflammatory lesions. Dapsone was effective in suppressing the skin and joint symptoms when metronidazole and/or tetracycline had failed.

Antigen-Antibody Complex↗
PubMed2006

Suppression of beta-amyloid precursor protein signaling into the nucleus by estrogens mediated through complex formation between the estrogen receptor and Fe65.

The C-terminal fragment of the beta-amyloid precursor protein produced after cleavage by gamma-secretase, namely, APPct or AICD, has been shown to form a multimeric complex with the adaptor protein Fe65 and to regulate transcription through the recruitment of the histone acetyltransferase Tip60. The present study shows that 17beta-estradiol inhibits the transcriptional and apoptotic activities of the APPct complex by a process involving the interaction of estrogen receptor alpha (ERalpha) with Fe65. ERalpha-Fe65 complexes were detected both in vitro and in the mouse brain, and recruitment of ERalpha to the promoter of an APPct target gene (KAI1) was demonstrated. Our studies reveal a novel mechanism of estrogen action, which may explain the well-known neuroprotective functions of estrogens as well as the complex role of this female hormone in the pathogenesis of neuronal degeneration diseases.

Amyloid beta-Protein Precursor↗
PubMed1989

Hormone binding site of the insulin receptor: analysis using photoaffinity-mediated avidin complexing.

A trifunctional reagent was designed which allows derivatization of ligands, particularly peptides and proteins, for subsequent photoaffinity labelling of receptors and specific isolation of the covalent complex or its fragments. B29-(2-nitro-4-azidophenyl)-biocytinyl-insulin (NB-insulin) was synthesized, radioiodinated, and the B26-mono-iodo derivative isolated by HPLC. It was used to photoaffinity label human placental membranes and the purified insulin receptor. Extensive digestion of the covalent insulin-receptor complex with trypsin (EC 3.4.21.4) led to the generation of a fragment of Mr 14,000. Specific complexing with avidin, derivatized avidin or streptavidin could be demonstrated for the photoaffinity labelled alpha-subunit and the 14,000 core fragment. The latter was isolated (approx. 100 pmol from 3-4 placentae) by streptavidin affinity chromatography and HPLC. According to microsequencing based on the known primary structure of the insulin receptor, the N-terminus of the core peptide appears to be Leu20-His21-Glu22-Leu23. We thus conclude: a part of the insulin-binding region of the receptor is located close to the N-terminus of its alpha-subunit in a remarkably stable domain of the sequence 20--(approx.) 120.

Affinity Labels↗
PubMed1992

'Pauci-immune' rapidly progressive glomerulonephritis associated with systemic vasculitis.

'Pauci-immune' glomerulonephritis has been recognized as an important cause of rapidly progressive glomerulonephritis. The paucity of immune deposits can be separated from the other two major immunohistologic variants of crescentic glomerulonephritis, ie, antiglomerular basement membrane (GBM) antibody-mediated and immune complex-mediated glomerulonephritis. Here we describe the case of a 42-year-old woman with pauci-immune' glomerulonephritis and vasculitis presenting as rapidly progressive renal failure with characteristic pathologic and immunohistologic findings. And in this case, despite oliguria and rapid deterioration of renal function, the renal function recovered partially and continued to be stabilized with a favourable response to hemodialysis and combined system immunosuppressive therapy.

Adult↗
PubMed2000

Tumor necrosis factor induced adhesion molecule serum concentrations in Henoch-Schönlein purpura and pediatric systemic lupus erythematosus.

OBJECTIVE: Animal models of immune complex mediated tissue injury have shown that tumor necrosis factor (TNF) and TNF induced adhesion molecules play an important role in the pathogenesis of tissue damage mediated by IgG, but not in that mediated by IgA, immune complexes. We compared possible differences in the behavior of 2 TNF induced adhesion molecules (VCAM-1 and ICAM-1) in Henoch-Schönlein purpura (HSP), which is characterized by the formation of IgA immune complexes, versus systemic lupus erythematosus (SLE), which is mostly associated with the vascular deposition of IgG immune complexes. METHODS: Serum concentrations of soluble (s)VCAM-1 and ICAM-1 were determined by ELISA methods in 20 patients with pediatric SLE showing variably active disease, 20 active patients with active HSP, and 19 healthy controls. TNF-alpha as well as p55 and p75 soluble receptors (sTNF-R) were simultaneously tested by enzyme amplified sensitivity immunoassay in 22 patients (12 SLE, 10 HSP). RESULTS: Serum sVCAM-1 concentration was significantly higher in patients with SLE (mean +/- SD, 608 +/- 76 ng/ml), than in patients with HSP (501.9 +/- 63.3 ng/ml) and controls (446.8 +/- 139.2 ng/ml) (p < 0.001). In SLE patients, sVCAM-1 correlated positively with ESR (r = 0.45, p = 0.02) and negatively with C4 serum levels (r = -0.57, p = 0.004), platelets (r = -0.38, p = 0.03), and lymphocyte count (r = -0.42, p = 0.03). No differences in sICAM-1 serum concentrations were detected among SLE, HSP, or control groups. Soluble VCAM, but not sICAM-1, showed a positive correlation with TNF-alpha (r = 0.71, p = 0.01), p55 (r = 0.63, p = 0.02), and p75 (r = 0.7, p = 0.01) sTNF-R serum concentrations in SLE, but not in patients with HSP. CONCLUSION: Our study provides additional evidence of a possible differential involvement of TNF and TNF induced adhesion molecules in the pathogenesis of tissue damage between pediatric SLE and HSP.

Adolescent↗
PubMed1985

Reduced complement-mediated immune complex solubilization in leprosy patients.

The ability of sera from leprosy patients to solubilize immune precipitates in vitro through the complement system was studied. The solubilizing capacity of sera from patients who did not have any reactions during 2 years or more after starting chemotherapy was comparable with that of normal laboratory volunteers. On the other hand, sera from borderline tuberculoid and lepromatous leprosy patients in reaction had markedly decreased levels of solubilization. Their total and the alternative pathway haemolytic levels did not show a corresponding decrease. Although the circulating immune complexes and serum C3d of these patients came down after the subsidence of reaction, their solubilization remained consistently low during a 3 month follow-up period.

Antigen-Antibody Complex↗
PubMed1997

Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor.

We recently demonstrated that gene-targeted disruption of the C5a anaphylatoxin receptor prevented lung injury in immune complex-mediated inflammation. In this study, we compare the effect of C5aR deficiency in immune complex-induced inflammation in the peritoneal cavity and skin with the results derived from our immune complex alveolitis model. C5aR- deficient mice exhibit decreased migration of neutrophils and decreased levels of TNF-alpha and interleukin 6 in the peritoneal reverse passive Arthus reaction compared to their wild-type littermates. In the reverse passive Arthus reaction in the skin the C5aR was also required for the full expression of neutrophil influx and edema formation; C5aR-deficient mice showed reduced neutrophil migration and microvascular permeability changes. In contrast to our studies in immune complex-induced lung inflammation, C5aR deficiency does not completely prevent injury in the peritoneal cavity and skin. These data indicate a dominant role for the C5aR and its ligand in the reverse passive Arthus reaction in the lung and a synergistic role together with other inflammatory mediators in immune complex-mediated peritonitis and skin injury.

Animals↗