Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator activity and plasmin-like amidolytic activity were investigated in two experimental rat tumours, using human plasminogen and chromogenic peptide substrate, S-2251. The invasive hepatocarcinoma and non-invasive nephroma were induced with the same chemical carcinogen, dimethylnitrosamine, in F-344 rats and they were continuously transplanted under the renal capsule. While there was no difference in plasmin-like activities of the tumours, the plasminogen activator activity was very low in the nephroma, but high in the hepatocarcinoma. Since the activator activity was completely inhibited by amiloride, it was considered to be of urokinase-type. These results were in accordance with the assumed role of urokinase in the invasion. However, of the respective control organ, kidney was rich in both activities but rat liver contained only very low activities. Therefore the comparison of the plasminogen activator activity of a tumour to the control organ probably does not provide information concerning the malignant transformation as it is suggested in the literature.
 ...
PMID:Plasminogen activator and plasmin-like activities in experimental rat tumours. 255 73

We have isolated three cDNA clones for human alpha 2-plasmin inhibitor (alpha 2-PI). Two clones are from human hepatoma cell line, Hep G2, and cover the entire protein coding region plus the 3'-flanking region up to the poly(A) sequence, and the other clone is from human liver and contains the carboxyl-terminal half. The total length of the cDNAs is 2.29 kb, corresponding to more than 95% of the full-length mRNA. alpha 2-PI seems to consist of 452 amino acid residues plus 39 amino acid residues for the signal peptide. The amino acid sequence shows 23 to 28% homology to those of five other protease inhibitors, plasminogen activator inhibitor (PAI), protein C inhibitor (PCI), alpha 1-antitrypsin (alpha 1-AT), antithrombin III (AT III), and alpha 1-antichymotrypsin (alpha 1-AC). alpha 2-PI seems to be the most distantly related among these inhibitors. Comparison of the phylogenetic trees of proteases and their inhibitors indicates that four proteases, namely elastase (or trypsin), chymotrypsin, plasminogen activator, and thrombin, may have evolved concurrently with the corresponding inhibitors. However, alpha 2-PI and PCI seem to have evolved asynchronously from their substrates. The data suggest that alpha 2-PI may originally have inhibited some protease other than plasmin, and protein C may have had an inhibitor different from the present one early in its evolutionary history.
 ...
PMID:Structure of human alpha 2-plasmin inhibitor deduced from the cDNA sequence. 283 Feb 48

Hemopexin alters conformation upon binding heme as shown by circular dichroism (CD), but hemopexin binds the heme analog, iron-meso-tetra-(4-sulfonatophenyl)-porphine (FeTPPS), without undergoing concomitant changes in its CD spectrum. Moreover, FeTPPS, unlike heme, does not increase the compactness of the heme-binding domain (I) of hemopexin shown by an increased sedimentation rate in sucrose gradients. On the other hand, like heme, FeTPPS forms a bishistidyl coordination complex with hemopexin and upon binding protects hemopexin from cleavage by plasmin. Competitive inhibition and saturation studies demonstrate that FeTPPS-hemopexin binds to the hemopexin receptor on mouse hepatoma cells but with a lower affinity (Kd 125 nM) more characteristic of apo-hemopexin than heme-hemopexin (Kd 65 nM). This provides evidence that conformational changes produced in hemopexin upon binding heme, but not upon binding FeTPPS, are important for increasing the affinity of hemopexin for its receptor. The amount of cell-associated radiolabel from 55FeTPPS-hemopexin increases linearly for up to 90 min but at a rate only about a third of that of the mesoheme-complex. As expected from the recycling of hemopexin, more iron-tetrapyrrole than protein is associated with the Hepa cells, but the ratio of 55Fe-ligand to 125I-hemopexin is only 2:1 for FeTPPS-hemopexin compared to 4:1 for mesoheme complexes. [55Fe]Mesoheme was associated at 5 min with lower density fractions containing plasma membranes and at 30 min with fractions containing higher density intracellular compartments. In contrast, 55FeTPPS was found associated with plasma membrane fractions at both times and was not transported into the cell. Although FeTPPS-hemopexin binds to the receptor, subsequent events of heme transport are impaired. The results indicate that upon binding heme at least three types of conformational changes occur in hemopexin which have important roles in receptor recognition and that the nature of the ligand influences subsequent heme transport.
 ...
PMID:Importance of ligand-induced conformational changes in hemopexin for receptor-mediated heme transport. 283

Incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone rapidly inhibits plasminogen activator (PA) activity secondary to the induction of a specific acid-stable inhibitor of plasminogen activation (Cwikel, B. J., Barouski-Miller, P.A., Coleman, P.L., and Gelehrter, T.D. (1984) J. Biol. Chem. 259, 6847-6851). We have further characterized this inhibitor with respect to its interaction with both urokinase and tissue plasminogen activator, and its protease specificity. The HTC PA inhibitor rapidly inhibits urokinase and tissue plasminogen activator with an apparent second-order rate constant of 3-5 x 10(7) M-1 X s-1. The inhibitor forms stable covalent complexes with both urokinase and tissue plasminogen activator, with which plasmin, trypsin, and factor Xa apparently do not compete. Complex formation is saturable and requires the active site of the PA. The mass of the inhibitor-PA complex is 50,000 daltons greater than that of PA alone, consistent with an Mr for the PA inhibitor of 50,000 as demonstrated directly by reverse fibrin autography. The HTC PA inhibitor does not inhibit thrombin and differs in its kinetic and biochemical properties from protease nexin.
 ...
PMID:Characterization of the dexamethasone-induced inhibitor of plasminogen activator in HTC hepatoma cells. 293 42

Bovine capillary endothelial cells have been found to respond to several stimuli by producing increased amounts of plasminogen activator and latent collagenase. These stimulators include the tumor promoter tetradecanoyl phorbol-13-acetate as well as crude preparations from a human hepatoma, bovine retinae, and mouse adipocytes, all of which are known to contain angiogenic factors. Endothelial cells and skin fibroblasts do not respond to these stimuli in the same way, indicating a specificity of the response. In addition, inhibitors of plasmin and vertebrate collagenase have been isolated from cartilage, a tissue resistant to neovascularization. We have proposed that these specific protease inhibitors confer on cartilage its antiangiogenic properties.
 ...
PMID:The involvement of proteases and protease inhibitors in neovascularization. 617 34

The capacity of the human hepatoma cell line Hep G2 to synthesize and secrete components of the fibrinolytic system was examined. Although fibrinogen, plasminogen, and alpha 2-antiplasmin were present in culture supernatants, histidine-rich glycoprotein was not detected. Albumin was monitored for comparative purposes and was also secreted. Intracellular levels of the fibrinolytic proteins were not detected, suggesting that once synthesized, these proteins were rapidly secreted by the cell. The fibrinogen, plasminogen, alpha 2-antiplasmin, and albumin secreted by the cells were immunochemically identical to their plasma counterparts. The concentration of these four molecules increased exponentially with time in the culture medium when normalized to total cellular protein. The kinetics of their secretion were similar, but the amounts of each protein differed. On day 8 the culture medium contained 29.6, 0.64, 0.39, and 0.59 micrograms/ml albumin, fibrinogen, plasminogen, and alpha 2-antiplasmin, respectively, whereas the time required for doubling the concentrations of the proteins in the medium ranged from 2.20 to 2.49 days. A detailed characterization of alpha 2-antiplasmin demonstrated that this inhibitor was synthesized by the cells. The molecular weight of intrinsically labeled alpha 2-antiplasmin was 69,000. The secreted inhibitor was biologically active, since it could inhibit plasmin cleavage of a chromogenic substrate, and this inhibition was neutralized by monospecific antibodies to alpha 2-antiplasmin. In addition, intrinsically labeled alpha 2-antiplasmin and the plasma molecule behaved in an identical manner with respect to their capacity to form a complex with plasmin. These studies suggest that the Hep G2 cell line may provide a model for assessing the regulation of synthesis and secretion of components of the human fibrinolytic system.
 ...
PMID:Synthesis and secretion of the fibrinolytic components, including alpha 2-antiplasmin, by a human hepatoma cell line. 618 56

A nephelometric method is described for determination of plasminogen and two types of plasmin inhibitors in human plasma having different affinity toward plasmin. This method is based on the kinetic analysis of effects of whole plasma and plasmin inhibitor fraction obtained from plasma on the activity of exogenously added plasminogen which was determined by measuring the decrease of light scattering of fibrin suspension. With this method we have determined the activity of plasminogen and two types of inhibitors in the plasma of normal subjects and patients with high fibrinogen degradation product values. They include patients with various malignant tumors with DIC, chronic renal failure, sepsis, vascular diseases, and liver cirrhosis with hepatoma.
 ...
PMID:Nephelometric determination of plasminogen and plasmin inhibitors in human plasma using fibrin suspension as a substrate. 622 10

The site of synthesis of alpha 2-plasmin inhibitor (alpha 2-PI), a physiologic inhibitor of plasmin, is not known with certainty. We have studied the production and secretion of alpha 2-PI by three established human liver cell lines derived from hepatocellular carcinoma and hepatoblastoma (Hep G2, Hep 3B, and PLC/PRF/5). As measured by a specific radioimmunoassay, the titer of alpha 2-PI increased in the medium of Hep G2 and Hep 3B cells with time, but no significant amount of alpha 2-PI was found in the medium of PLC/PRF/5. There was no evidence for a significant intracellular pool of this protein. On immunodiffusion against anti-alpha 2-PI serum, alpha 2-PI secreted by Hep G2 (G2 alpha 2-PI) formed a simple precipitin line of complete identity with the alpha 2-PI present in plasma (plasma alpha 2-PI). G2 alpha 2-PI behaved similarly to plasma alpha 2-PI in Sephadex G-150 gel filtration, sucrose density-gradient centrifugation, and crossed immunoelectrophoresis. G2 alpha 2-PI inhibited plasmin activity instantaneously in a functional assay and formed a complex with plasmin demonstrable by crossed immunoelectrophoresis. De novo synthesis of alpha 2-PI was shown by the presence of specific immunoprecipitable radioactivity in the medium after 5 hr of labeling of the cells with [35S]methionine. Analysis of the immunoprecipitates by NaDodSO4/polyacrylamide gel electrophoresis showed a single peak of radioactivity corresponding to Mr 68,000. These results indicate that the liver is a site of alpha 2-PI production.
 ...
PMID:Synthesis and secretion of alpha 2-plasmin inhibitor by established human liver cell lines. 629 Oct 58

Plasminogen activators are membrane-associated, arginine-specific serine proteases which convert the inactive plasma zymogen plasminogen to plasmin, an active, broad-spectrum serine protease. Plasmin, the major fibrinolytic enzyme in blood, also participates in a number of physiologic functions involving protein processing and tissue remodelling, and may play an important role in tumor invasion and metastasis. In HTC rat hepatoma cells in tissue culture, glucocorticoids rapidly decrease plasminogen activator (PA) activity. We have shown that this decrease is mediated by induction of a soluble inhibitor of PA activity rather than modulation of the amount of PA. The hormonally-induced inhibitor is a cellular product which specifically inhibits PA but not plasmin. We have isolated variant lines of HTC cells which are selectively resistant to the glucocorticoid inhibition of PA but retain other glucocorticoid responses. These variants lack the hormonally-induced inhibitor; PA from these variants is fully sensitive to inhibition by inhibitor from steroid-treated wild-type cells. Cyclic nucleotides dramatically stimulate PA activity in HTC cells in a time- and concentration-dependent manner. Paradoxically, glucocorticoids further enhance this stimulation. Thus glucocorticoids exert two separate and opposite effects on PA activity. The availability of glucocorticoid-resistant variant cell lines, together with the unique regulatory interactions of steroids and cyclic nucleotides, make HTC cells a useful experimental system in which to study the multihormonal regulation of plasminogen activator.
 ...
PMID:Hormonal regulation of plasminogen activator in rat hepatoma cells. 631 82

Dexamethasone induces an inhibitor of plasminogen-dependent fibrinolysis in rat hepatoma (HTC) cells. The specificity of the inhibitor for urokinase and plasmin was investigated using both fibrinolytic and esterolytic assays. Urokinase, but not plasmin, was inhibited by serum-free conditioned medium from cells incubated with 0.1 microM dexamethasone. The specificity of the inhibitor for plasminogen activator was demonstrated directly by the inhibition of the urokinase-catalyzed activation of 125I-plasminogen to 125I-plasmin. The inhibitory activity was stable to pH 3 for 2 h at 37 degrees C, a condition which inactivated fibrinolytic inhibitors in serum, suggesting a cellular origin for the inhibitor. Further evidence for the cellular origin was the constant daily production of inhibitor throughout a 4-day incubation with dexamethasone in serum-free medium. SF HTC-H1 cells, selected for their ability to grow in serum-free medium (Thompson, E. B., Anderson, C. U., and Lippman, M. E. (1975) J. Cell Physiol. 86, 403-412), were grown for 76 days (at least 30 generations) in the presence or absence of serum; dexamethasone induced equivalent amounts of inhibitory activity in cells which had been grown under both conditions. We conclude that the dexamethasone-induced inhibitor from HTC cells is a cellular product which is specific for the inhibition of plasminogen activation and which differs from other reported fibrinolytic inhibitors.
 ...
PMID:The dexamethasone-induced inhibitor of fibrinolytic activity in hepatoma cells. A cellular product which specifically inhibits plasminogen activation. 646 54


<< Previous 1 2 3 4 5 Next >>