Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic expression of various members of the cytochrome P-450 (CYP) superfamily is suppressed during inflammatory responses. We have shown that the specific expression of P-450 2C11 in male rat liver is suppressed transcriptionally by endotoxin treatment. To investigate the molecular mechanisms underlying this phenomenon, we studied the effects of the inflammatory cytokines interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF), interferon (IFN)-alpha, and IFN-gamma on the expression of P-450 2C11 and the mRNAs of two typical acute-phase protein genes, alpha 1-acid glycoprotein (AGP) and fibrinogen, in primary hepatocyte cultures. IL-1, IL-6, TNF, and IFN-alpha all suppressed P-450 2C11 mRNA, whereas IFN-gamma had no effect. IL-1 and TNF were more effective than IL-6 in the suppression of P-450 2C11 mRNA. Whereas IL-1 and IL-6 effects on P-450 2C11 were accompanied by induction of AGP and fibrinogen mRNAs, IFN-alpha and TNF treatments had no effects on AGP. The suppression of P-450 2C11 and the induction of AGP by IL-1 showed similar time courses. The combination of IL-1 and IL-6 showed additivity in suppression of P-450 2C11, at maximally effective concentrations of cytokines. The effects of IL-1 on P-450 2C11 and AGP expression were blocked by IL-1 receptor antagonist protein. We also studied the effects of IL-1 and IL-6 on the transient expression of chloramphenicol acetyl-transferase reporter gene constructs containing 200 or 1287 base pairs of the 5' flanking region of the CYP2C11 gene, transfected into primary hepatocytes. The chloramphenicol acetyltransferase activities in cells transfected with the 200-base pair construct were reduced to about 33% and 58% of control levels by treatment with IL-1 or IL-6, respectively, suggesting that sequences important for cytokine down-regulation lie within the proximal promoter region of the CYP2C11 gene.
Mol Pharmacol 1995 May
PMID:Suppression of the constitutive expression of cytochrome P-450 2C11 by cytokines and interferons in primary cultures of rat hepatocytes: comparison with induction of acute-phase genes and demonstration that CYP2C11 promoter sequences are involved in the suppressive response to interleukins 1 and 6. 753 97

Immunocytochemistry with gold-labeled antibodies was used to compare the effects of stimulation of human platelets with thrombin (1 U/ml) and the thrombin receptor activating peptide, SFLLRN (20 microM). After 3 min, redistribution of fibrinogen, von Willebrand factor, and P-selectin (GMP-140, CD62) was examined, the percentages of [14C]serotonin and beta-thromboglobulin released from pre-labeled platelets were measured, and the amount of thromboxane B2 formed was assayed. Upon stimulation with either thrombin or SFLLRN, the platelets had changed from their normal disc shape to spheroidal forms with short pseudopodia. Few alpha-granules remained, the open canalicular system was expanded (more so with SFLLRN) and contained most of the fibrinogen and von Willebrand factor, although small amounts were evident on the platelet surface. Most of the P-selectin was on the surface. Both thrombin and SFLLRN caused complete release of beta-thromboglobulin and 88.3 and 77.5% release of [14C]serotonin, respectively. However, formation of TXB2 caused by thrombin was 10 times greater than that caused by SFLLRN (969 +/- 173 vs 76 +/- 22 ng/10(9) platelets). Thus, the redistribution of platelet alpha-granule contents is similar with thrombin or SFLLRN stimulation and is unaffected by the extent of thromboxane formation.
Exp Mol Pathol 1995 Feb
PMID:Effects of thrombin and the thrombin receptor activating peptide, SFLLRN, on redistribution of platelet alpha-granule contents are similar and independent of the extent of thromboxane formation. 755 92

The mutation of Gly12 to Val12 in the A alpha chains of human fibrinogen Rouen is associated with a delayed proteolytic release of fibrinopeptide A (FpA or A alpha 1 to 16 of fibrinogen) by thrombin, leading to a bleeding disorder. Analogs of FpA and FpA Rouen have been designed that include a Pro15 to replace Val15 in natural FpA and to mimic the frequent occurrences of a proline residue at equivalent positions of other protein substrates of thrombin. The Pro15 analogs of FpA and FpA Rouen bind specifically to the active site of thrombin as shown by thrombin-induced differential line broadening and transferred nuclear Overhauser effects (transferred NOEs). Pro15 is well tolerated by the thrombin-bound structures of both FpA and FpA Rouen in solution, resulting in enhanced conformational stabilities of the thrombin-FpA complexes. The Val12 mutation in FpA Rouen causes backbone conformational changes in residues Val12 and Gly13 accompanied by an expansion of the hydrophobic cluster of FpA to accommodate the bulky side-chain of Val12. The single turn of helical structure between residues Asp7 and Glu11 is stabilized by hydrogen bonds from the side-chain carboxylate of Asp7 to the exposed backbone NH groups of Ala10 and/or Leu9 (N-capping), and by hydrogen bonds between the exposed backbone carbonyl groups of residues Phe8 and Leu9, and the backbone NH groups of Gly12/Val12 and Gly13 (C-capping). The bound structure of FpA Rouen may be further stabilized by a non-polar (i,i + 4) interaction between the aromatic side-chain of Phe8 and the aliphatic side-chain of Val12. Despite these optimized intrapeptide interactions, the thrombin-peptide interactions are highly dynamic as indicated by the fast rate of dissociation (koff > 100 s-1) of the peptide ligands from the thrombin complexes. Sequence comparison between mammalian fibrinopeptides A and B suggests that the specificity of thrombin is dictated by a four-residue consensus motif, Phe(P4)-Xxx(P3)-Pro(P2)-Arg(P1) or FXPR, when Xxx at P3 can be a charged or a neutral polar residue capable of specific interactions with residues near the active site of thrombin.
J Mol Biol 1995 Oct 06
PMID:Thrombin-bound structures of designed analogs of human fibrinopeptide A determined by quantitative transferred NOE spectroscopy: a new structural basis for thrombin specificity. 756 81

Intra-alveolar clot formation is a common finding in acute and chronic inflammatory lung diseases. Incorporation of lipophilic surfactant components into a growing fibrin clot has recently been reported (Am. J. Respir. Cell Mol. Biol. 1993; 9:213-220). In the present study, we investigated the influence of such surfactant incorporation on the elastic properties and water permeability of the fibrin polymer. Thrombelastography and compaction experiments were employed for assessment of the elastic properties, and the permeability characteristics of the clot material were addressed in fibrin-packed columns. Two calf lung surfactant extracts (CLSE and Alveofact), Curosurf, and a synthetic phospholipid mixture (dipalmitoylphosphatidylcholine, phosphatidylglycerol, and palmitic acid at a ratio of 68.5:22.5:9 [wt/wt]) were used. The presence of surfactant did not affect the cleavage of fibrinopeptide A upon incubation of fibrinogen with thrombin (enzyme-linked immunosorbent assay technique). Similarly, kinetics and extent of factor XIII-induced covalent crosslinkage of the fibrin network remained unchanged in the presence of surfactant (sodium dodecyl sulfate polyacrylamide gel electrophoresis and D-Dimer quantification upon subsequent clot lysis). All surfactants, however, dose-dependently decreased the elastic modulus of the arising fibrin polymer. The maximal amplitude in thrombelastography was reduced, and the recovery of fluid after centrifugation of the fibrin clot increased. Fibrin clots embedding natural surfactant material displayed reduced permeability for saline as compared with control fibrin polymers. Subsequent washout of lipids from these clots with Triton X-100 resulted in increased hydraulic conductivity. This was accompanied by an increase in pore size, suggesting altered architecture of the fibrin matrix generated in the presence of surfactant.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Dec
PMID:Surfactant incorporation markedly alters mechanical properties of a fibrin clot. 757 9

The potentiophotometer (PTPH) is a spectrophotometric device that embodies the electrical, analog solution to Beer's Law. The output of the instrument gives, directly and simultaneously, the concentration of the substance being measured. The PTPH has been applied to the manual determination of fibrinogen (FBG) with the same thrombopalstin injection as the prothrombin time (PT). We have now semi-automated and computerized the PTPH to constitute the coagulation instrument named POTENS+. POTENS+ determines the FBG rapidly, within approximately three to twenty seconds after the PT. With POTENS+, precision, linearity and reference range will be given for its FBG method. The accuracy of POTENS+ will be assessed by comparing it with both automated FBG methods on the MLA Electra 1000C Coagulation Timer. Of these two methods, the automated Clauss method is used as the reference method.
Res Commun Mol Pathol Pharmacol 1995 Jul
PMID:Rapid fibrinogen determination with the prothrombin time using a potentiophotometer. 758 63

We have previously shown that soluble partially degraded fibrin(ogen) remains in solution after fibrin clot formation and is a potent fibroblast mitogen (Gray, A.J., Bishop, J.E., Reeves J.T., Mecham, R.P., and Laurent, G.J. (1995) Am. J. Cell Mol. Biol. 12, 684-690). Mitogenic sites within the fibrin(ogen) molecule are located on the A alpha and B beta chains of the protein (Gray, A.J., Bishop, J. E., Reeves, J.T., and Laurent, G.J. (1993) J. Cell Sci. 104, 409-413). However, receptor pathways through which mitogenic effects are mediated are unknown. The present study sought to determine the nature of fibrin(ogen) receptors expressed on human fibroblasts which interact with the fibrinogen B beta chain. Receptor complexes were isolated from 125I-surface-labeled fibroblasts and purified on a fibrinogen B beta chain affinity column. Subsequent high performance liquid chromatography and SDS-polyacrylamide gel electrophoresis analysis indicated fibrinogen B beta chain bound specifically to a 60-kDa surface protein. Sequence analysis of the amino terminus of this protein indicated 100% homology to human calreticulin. Immunoprecipitation experiments employing a polyclonal anti-calreticulin antibody provided further evidence that the 60-kDa protein isolated in this study was calreticulin. Further, polyclonal antibodies to human calreticulin significantly inhibited the mitogenic activity of fibrinogen B beta chain on human fibroblasts. The present study has shown that cell surface calreticulin binds to the B beta chain of fibrinogen mediating its mitogenic activity.
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PMID:The mitogenic effects of the B beta chain of fibrinogen are mediated through cell surface calreticulin. 759 83

The thrombocyte is the avian equivalent of the mammalian blood platelet and is involved in hemostasis through a fibrinogen-mediated process. Although fibrinogen has been implicated as a molecular bridge between activated cells during aggregation, the location of this molecule and its receptor on thrombocytes has not been characterized. Pigeon fibrinogen, isolated from plasma by precipitation with PEG-1000 and purified over Sepharose 4B, was used to study receptor-ligand interaction. Separation of pigeon fibrinogen on SDS-PAGE resulted in three peptides of molecular mass 62, 55, and 47 kDa, which were comparable to those of human fibrinogen. The role of fibrinogen and its receptor in thrombocyte function was established by turbidimetric aggregation using thrombin as an agonist under conditions requiring Ca2+ and fibrinogen. Maximum response occurred using 3 mM Ca2+ and 100 micrograms/ml fibrinogen. Fibrinogen-dependent aggregation was inhibited by an anti-GPIIb antibody, verifying a role for fibrinogen receptors in thrombocyte function. Fibrinogen-gold conjugates were used to describe receptor and ligand localization on aggregated cells. Computer reconstruction was used to verify relocalization of fibrinogen receptors following activation. Fibrinogen distribution changed from a dispersed state in preactivated cells to focal localization at points of cell contact and along pseudopods following activation. This selective positioning of fibrinogen suggests that a functional relocalization of the receptor occurs upon thrombocyte activation, and this relocation facilitates the role of fibrinogen as a molecular bridge. These studies establish similarities between the avian and the human systems and document the conserved nature of the hemostatic process.
Exp Mol Pathol 1994 Dec
PMID:Localization of fibrinogen during aggregation of avian thrombocytes. 760 Dec 70

In a variety of diseases including asthma, inflammation causes microvascular leakage and activates thrombin. In addition to cleaving fibrinogen to fibrin, thrombin may have other important cellular effects. Because airway inflammation and vascular permeability are important determinants of airway hyperreactivity, we have studied the effects of thrombin on airway smooth muscle. Using cultured human airway smooth muscle cells, we have examined whether alpha-thrombin can evoke calcium responses, phosphoinositide turnover, or cell proliferation. We have demonstrated that alpha-thrombin does increase cytosolic calcium and phosphoinositide hydrolysis in a dose- and time-dependent manner that may be inhibited by pretreating cells with r-hirudin. In addition, we have shown that thrombin stimulates airway smooth muscle cell proliferation. By contrast, bradykinin, which evoked comparable increases in cytosolic calcium and phosphoinositide turnover, did not stimulate airway smooth muscle cell growth. We conclude that thrombin effectively increases cytosolic calcium and induces PI hydrolysis and, in addition, is capable of stimulating airway smooth muscle cell growth. However, the lack of an effect of bradykinin on cell growth suggests that increases in calcium and PI turnover alone will not induce airway smooth muscle cell proliferation. We suggest that alpha-thrombin may be important in the pathogenesis of both increased airway resistance as well as the structural changes seen as a consequence of chronic asthma.
Am J Respir Cell Mol Biol 1995 Aug
PMID:alpha-Thrombin increases cytosolic calcium and induces human airway smooth muscle cell proliferation. 762 88

Two antigenic classes of non-immune IgG-binding proteins can be expressed by group A streptococci. One antigenic group of proteins is recognized by an antibody prepared against the product of a cloned fcrA gene (anti-FcRA). In this study, the immunogen used to prepare the antibody that defines the second antigenic class was shown to be the product of the emm-like (emmL) gene of M serotype 55 group A isolate, A928. The emmL55 gene expressed in E. coli produced an M(r) approximately 58,000 molecule which bound human IgG1, IgG2, IgG3 and IgG4, as well as horse, rabbit and pig IgG in a non-immune fashion. These properties are characteristic of the previously described type IIo IgG-binding protein isolated from this strain. In addition, the recombinant protein was reactive with human serum albumin and fibrinogen. The emmL 55 gene sequence was analysed and found to have the organization and sequence characteristics of a typical class I emm-like gene.
Mol Immunol 1995 Jun
PMID:Characterization of a gene coding for a type IIo bacterial IgG-binding protein. 764 59

Interleukin-6 (IL-6) is known to be a major mediator of the acute-phase response in liver. We show here that IL-6 triggers the rapid activation of a nuclear factor, termed acute-phase response factor (APRF), both in rat liver in vivo and in human hepatoma (HepG2) cells in vitro. APRF bound to IL-6 response elements in the 5'-flanking regions of various acute-phase protein genes (e.g., the alpha 2-macroglobulin, fibrinogen, and alpha 1-acid glycoprotein genes). These elements contain a characteristic hexanucleotide motif, CTGGGA, known to be required for the IL-6 responsiveness of these genes. Analysis of the binding specificity of APRF revealed that it is different from NF-IL6 and NF-kappa B, transcription factors known to be regulated by cytokines and involved in the transcriptional regulation of acute-phase protein genes. In HepG2 cells, activation of APRF was observed within minutes after stimulation with IL-6 or leukemia-inhibitory factor and did not require ongoing protein synthesis. Therefore, a preexisting inactive form of APRF is activated by a posttranslational mechanism. We present evidence that this activation occurs in the cytoplasm and that a phosphorylation is involved. These results lead to the conclusions that APRF is an immediate target of the IL-6 signalling cascade and is likely to play a central role in the transcriptional regulation of many IL-6-induced genes.
Mol Cell Biol 1993 Jan
PMID:Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. 767 52


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