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

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.
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PMID:Hormonal regulation of plasminogen activator in rat hepatoma cells. 631 82

We have reported previously that derivatives of adenosine cyclic 3':5'-monophosphate dramatically stimulate the activity of plasminogen activator (PA), an arginine-specific serine protease, in HTC rat hepatoma cells. We report here that these derivatives also cause striking alterations in hepatoma tissue culture cell morphology. Because PA has been shown to alter cell morphology in other cell lines, we investigated whether the morphological changes induced by cyclic nucleotides were mediated by the stimulation of PA activity. Alterations in PA activity, measured by the plasminogen-dependent solubilization of 125I-labeled fibrin, and in cell morphology, detected by evaluation of cell flattening and process extension with phase-contrast microscopy, were assessed in the same cultures under various experimental conditions. Several lines of evidence clearly dissociate these two adenosine cyclic 3':5'-monophosphate-mediated phenomena. (a) The morphological changes precede increases in either cell-associated or extracellular PA activity. (b) Upon removal of the effectors, the morphological effects are completely reversed at a time when PA activity is still considerably elevated. (c) when protein synthesis is inhibited by the addition of cycloheximide, the stimulation of PA activity by cyclic nucleotides is blocked completely, whereas the induction of morphological alterations still occurs. (d) An exogenous PA, urokinase, does not elicit the characteristic changes in cell shape. We conclude that the morphological alterations induced by adenosine cyclic 3':5'-monophosphate derivatives in HTC cells are not mediated by the stimulation of PA activity and that these two membrane-associated properties are regulated independently.
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PMID:Role of plasminogen activator in the morphological alterations induced by derivatives of adenosine cyclic 3':5'-monophosphate in hepatoma tissue culture cells. 631 21

A protease active with N-alpha-benzoyl-DL-arginine-p-nitroanilide with an optimum pH of 7.3 has been found in the cytosol of rat liver. The activity of this protease increased in N-2-fluorenylacetamide-induced hepatoma as well as in fetal liver. It has been purified from normal liver and hepatoma about 200-fold. Its molecular weight is estimated by gel filtration to be about 200,000 in each tissue. The protease activity is unaffected by chymostatin, pepstatin, soybean trypsin inhibitor, and p-chloromercuribenzoate. Antipain, leupeptin, tosyl-L-lysine chloromethyl ketone, and phenylmethylsulfonyl fluoride inhibit the protease activity. This protease appears to be a serine protease.
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PMID:Increased activity of a neutral protease in cytosol from rat hepatoma induced by N-2-fluorenylacetamide. 703 Apr 84

Protein C inhibitor (PCI), a plasma serine protease inhibitor, neutralizes activated protein C, which plays an important role in the regulation of blood coagulation. We determined the organization of the gene coding for this inhibitor. A human genomic phage DNA library was screened using the 32P-labeled protein C inhibitor cDNA as a probe and a phage genomic clone that contained the full length of the inhibitor gene, including the 5'- and 3'-flanking region, was isolated. The gene was characterized by restriction enzyme mapping, Southern blotting and sequencing all the coding parts as well as the 5'- and 3'-flanking regions. The protein C inhibitor gene spanned about 13 kilobase pairs and consisted of 5 exons and 4 introns as do the genes for human alpha 1-antitrypsin, alpha 1-antichymotrypsin, heparin cofactor II and rat angiotensinogen. All exon-intron boundaries agreed with the GT-AG rule. The 5'-flanking region contained no TATAA or CCAAT sequences, but contained the putative Sp-1 and AP-2 binding sites in the 5'-upstream region, which indicated promoter activity in human hepatoma cell line, HepG2, using the luciferase gene as a reporter gene and the polyadenylation site in the 3'-downstream region. A transcription initiation site was identified by primer extension analysis using template human liver poly(A)RNA. The length of the non-coding exon I of this inhibitor gene was similar to those of the other serine protease inhibitors as described above. These findings suggest that the protein C inhibitor gene evolved from a common ancestor gene of these serine protease inhibitors.
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PMID:Gene organization of human protein C inhibitor, a member of SERPIN family proteins encoded in five exons. 814 99

Hepsin was previously identified as a putative cell-surface serine protease. When hepatoma cells were treated with anti-hepsin antibodies, their growth was substantially arrested, suggesting the requirement of hepsin molecules present at the cell surface for normal cell growth. This was further supported by a gross inhibition of cell growth with hepsin-specific antisense oligonucleotides. Upon treatment of cells with antisense oligonucleotides, rapid reduction in cellular hepsin was observed. This reduction in cellular hepsin levels was accompanied by drastic morphological changes. Various tissues in the developing mouse embryo showed greatly elevated hepsin levels in regions of active proliferation. These results indicate that hepsin plays an essential role in cell growth and maintenance of cell morphology.
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PMID:Hepsin, a putative cell-surface serine protease, is required for mammalian cell growth. 834 33

Tissue-type plasminogen activator (t-PA) is a plasma serine protease that catalyzes the initial and rate-limiting step in the fibrinolytic cascade. t-PA is widely used as a thrombolytic agent in the treatment of acute myocardial infarction. However, its use has been impaired by its rapid hepatic clearance from the circulation following intravenous administration. Studies with both rat hepatoma MH1C1 cells (G. Bu, S. Williams, D. K. Strickland, and A. L. Schwartz, 1992. Proc. Natl. Acad. Sci. USA. 89:7427-7431) and human hepatoma HepG2 cells (G. Bu, E. A. Maksymovitch, and A. L. Schwartz. 1993. J. Biol. Chem. 28:13002-13009) have shown that binding of t-PA to its clearance receptor, the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor, is inhibited by a 39-kD protein that copurifies with this receptor. Herein we investigated whether administration of purified recombinant 39-kD protein would alter t-PA clearance in vivo. We found that intravenous administration of purified 39-kD protein to rats prolonged the plasma half-life of 125I-t-PA from 1 min to approximately 5-6 min. The plasma half-life of t-PA enzymatic activity was similarly prolonged following intravenous administration of purified 39-kD protein. In addition we found that the 39-kD protein itself was rapidly cleared from the circulation in vivo. Clearance of 125I-39-kD protein was a biphasic process with half-lives of 30 s and 9 min and the liver was the primary organ of clearance. Preadministration of excess unlabeled 39-kD protein slowed 125I-39-kD protein clearance in rats in a dose-dependent manner, suggesting that specific clearance receptors were responsible for this process. Administration of increasing doses of unlabeled 39-kD protein along with labeled 39-kD protein resulted in a decrease in the amount of labeled 39-kD protein associating with the liver and a concomitant increase in the amount of labeled 39-kD protein associating with the kidneys, indicating two clearance mechanisms exist for the 39-kD protein.
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PMID:39-kD protein inhibits tissue-type plasminogen activator clearance in vivo. 834 26

Coagulation factor Xa is a plasma serine protease that catalyzes prothrombin to thrombin conversion, which, in turn, leads to the generation of the fibrin clot. Of the several parameters that govern the plasma level of factor Xa, control of its catabolism is of crucial importance. However, little is known regarding the mechanisms by which factor Xa is catabolized. In the present study we examine the cellular basis for the uptake and degradation of factor Xa. 125I-Factor Xa was degraded by hepatoma cells and embryonic fibroblasts via a process which required cell surface-bound tissue factor pathway inhibitor (TFPI), a potent inhibitor of factor Xa. Uptake and degradation of cell surface-bound 125I-TFPI was also markedly stimulated in response to factor Xa binding. The intracellular kinetics of 125I-factor Xa and cell surface-bound 125I-TFPI display a strikingly similar pattern, suggesting that factor Xa and cell surface-bound TFPI are taken up as a bimolecular complex. Using cell lines either deficient in low density lipoprotein receptor-related protein, an endocytic receptor that mediates the degradation of uncomplexed TFPI (Warshawsky, I., Broze, G.J., Jr., and Schwartz, A.L. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 6664-6668), or deficient in tissue factor (TF), an integral membrane protein capable of forming quarternary complexes with factor Xa, TFPI, and factor VIIa, we demonstrated that the receptor that mediates the uptake and degradation of factor Xa-TFPI complex was neither low density lipoprotein receptor-related protein nor TF. As the vascular endothelial cell surface retains a substantial pool of TFPI (Sandset, P.M., Alildgaard, U., and Larsen, M.L. (1988) Thromb. Res. 50, 803-813; Novotny, W.F., Brown, S.G., Miletich, J.P., Rader, D.J., and Broze, G.J., Jr. (1991) Blood 78, 387-393), our data suggest that endothelial cell surface TFPI may be actively involved in the clearance of factor Xa from the circulation via mediated uptake and degradation.
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PMID:Receptor-mediated endocytosis of coagulation factor Xa requires cell surface-bound tissue factor pathway inhibitor. 862 21

The low density lipoprotein receptor-related protein (LRP) has been proposed to function as an endocytosis receptor for chylomicron remnants and protease-inhibitor complexes so that these particles can be cleared from the plasma or extracellular fluid. The kidney glycoprotein 330 (gp330) may have an analogous role to LRP in the kidney. A 39-kDa protein which copurifies with LRP and gp330 inhibits the binding and/or cellular uptake of ligands to these receptors and may regulate LRP and gp330 activity in vivo. Recently, LRP has been immunochemically localized to endothelial and vascular smooth muscle cells. In the present study, the biology of the 39-kDa protein was studied in cultured endothelial cells and vascular smooth muscle cells. The 39-kDa protein is synthesized by both cell types and has an average half-life of 15 hours. Immunofluorescence shows the major part of the 39-kDa protein has an intracellular localization with enrichment in the perinuclear region. Tissue-type plasminogen activator (t-PA), a plasma serine protease that binds specifically and with high affinity to LRP on hepatoma cells, also binds to endothelial cells and vascular smooth muscle cells. 125I-t-PA binding to both cell types is inhibited by the 39-kDa protein. However, only the endothelial cells are capable of rapidly internalizing and degrading 125I-t-PA. These data thus suggest that LRP may function as a clearance receptor for t-PA on endothelial cells.
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PMID:The 39-kDa protein regulates LRP activity in cultured endothelial and smooth muscle cells. 890 16

Ra reactive factor, a lectin present in the sera of a wide variety of vertebrates, is composed of mannan-binding proteins and a serine protease termed P100, which is known to activate complement. Using differential mRNA display technology to study the "activation"-dependent gene expression of hepatic stellate cells (HSC), we partially cloned a cDNA encoding the rat homolog of P100, which displayed 94% and 88% homology to mouse and human P100 cDNA, respectively. In the rat P100, specific transcripts 5.4, 4.0, and 3.3 kb in size were detected in major amounts in normal liver, but were absent or near the detection limit in other organs. Among the different liver cell populations studied during primary culture, P100-specific transcripts of 4.0 kb were prominent in HSC and present in hepatocytes and hepatoma cells, whereas Kupffer cells and sinusoidal endothelial cells were P100-negative. In addition to 4.0-kb mRNA, freshly isolated hepatocytes also contained transcripts of 5.4 and 3.3 kb, which were down-regulated during primary culture. In situ hybridization of normal liver tissue confirmed the in vitro data in that P100 was expressed by hepatocytes and nonparenchymal liver cells, which probably represent HSC. In vitro P100 steady-state mRNA levels of hepatocytes were stimulated by IL-6 and/or dexamethasone. During the acute phase reaction induced by turpentine injection, P100 steady-state mRNA levels were up-regulated in rat liver. The data demonstrate that: (a) the liver is the primary site for P100 expression in the rat; (b) HSC and hepatocytes appear to represent the cellular sources; and (c) P100 steady-state mRNA levels are up-regulated by the acute phase mediators IL-6 and dexamethasone in vitro and during the acute phase reaction in vivo, suggesting that P100 represents a novel, positive acute-phase gene in the rat.
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PMID:The complement-activating protease P100 is expressed by hepatocytes and is induced by IL-6 in vitro and during the acute phase reaction in vivo. 931 46

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Therapeutic options for hepatitis C are limited. Standard monotherapy with interferon-alpha leads to a sustained response in only 10-20% of patients. Recent studies have shown improved sustained response rates for the combination of interferon-alpha and ribavirin. Despite these improvements, more effective therapies are needed. A variety of alternative agents are currently being evaluated in clinical trials. Recent advances in the molecular virology of hepatitis C have identified specific antiviral targets such as the viral NS3 serine protease, the RNA helicase, and the RNA-dependent RNA polymerase. In addition, gene therapeutic strategies aimed at inhibiting HCV gene expression and replication as well as immunotherapeutic concepts aimed at enhancing the cellular immune response against HCV are being explored in various experimental systems. These and other novel antiviral strategies may complement the existing therapeutic modalities in the future.
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PMID:Current and evolving therapies for hepatitis C. 1056 26


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