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)

We have reported previously that the phosphoprotein pp63, an acute phase protein, which has been recently identified as the rat fetuin, was capable of blocking the mitogenic effect of insulin on the rat Fao hepatoma cell line, without affecting metabolic effects of the hormone. Only the phosphorylated form of the protein has been shown to exhibit both anti-tyrosine kinase and growth inhibitory properties. In this study, we used the FTO-2B rat hepatoma cell line to analyze the mechanisms involved in the control of synthesis and/or phosphorylation of pp63. For this purpose, we investigated the action of effectors known to modulate hepatic functions, such as cytokines (interleukin (IL)-1 beta and IL-6), which regulate the production of acute phase proteins, and insulin, which elicits profound effects on hepatocyte metabolism. Here, we demonstrate that IL-1 beta diminished markedly the pp63 production by affecting its mRNA transcription and that the cytokine was able to modify the N-glycosylation process of the protein. In contrast, insulin did not affect the biosynthesis of pp63 but dramatically decreased its extent of phosphorylation.
 ...
PMID:Insulin and interleukin-1 differentially regulate pp63, an acute phase phosphoprotein in hepatoma cell line. 751 65

The receptor for granulocyte colony stimulating factor (G-CSFR) and chimeric receptors consisting of the extracellular domain of G-CSFR and the transmembrane and cytoplasmic domain of the leukemia inhibitory factor receptor, gp130, or c-mpl function as homodimeric complexes. These receptors mediate a similar stimulation of gene transcription via separate regulatory elements of acute phase plasma protein genes. To identify the receptor regions within the cytoplasmic domains necessary for transcriptional regulation, the receptors were transiently expressed in rat hepatoma cells. Each receptor form reconstituted G-CSF-induced expression of a chloramphenicol acetyltransferase gene construct containing the cytokine response element of the rat alpha 1-acid glycoprotein gene. This regulation required the presence of two conserved sequence motifs (referred to as box 1 and box 2) in the cytoplasmic domains of each receptor. With the exception of G-CSFR-MPL chimera, the receptors also mediated a similarly high stimulation via the IL-6 response element of the rat beta-fibrinogen and hemopexin genes. Regulation of the IL-6 response element required, however, in addition to boxes 1 and 2, a third sequence motif (box 3). This motif is absent in the cytoplasmic domain of c-mpl, possibly explaining its inability to activate the IL-6 response element. When cells which express receptor forms with prominent box 3 function were treated with suramin, a ligand-independent gene stimulation via the IL-6 response element was observed. The suramin effect probably involves a receptor dimerization mediated by the extracellular G-CSFR domain and by the intracellular regions that include box 3.
 ...
PMID:Signaling by the cytoplasmic domain of hematopoietin receptors involves two distinguishable mechanisms in hepatic cells. 751 79

TNF-stimulated gene-14 (TSG-14) encodes a secreted glycoprotein with significant sequence homology to C-reactive protein (CRP) and serum amyloid P component (SAP), members of the pentraxin family of acute phase proteins. TSG-14 mRNA was elevated in human FS-4 fibroblasts by treatment with TNF, IL-1, or bacterial LPS, and weakly by dexamethasone. Abs to recombinant TSG-14 immunoprecipitated a 42-kDa protein from the culture supernatants of TNF- or IL-1-stimulated FS-4 cells. TSG-14 protein was also inducible in the Hep3B human hepatoma cell line by TNF, IL-1, IL-6, or dexamethasone. CRP protein, identified by immunoprecipitation of a 25-kDa band with Abs to CRP, was induced in Hep3B cells by IL-1, IL-6, or dexamethasone. Immunoprecipitations with polyclonal Abs to TSG-14 and CRP suggested that the two proteins are immunologically cross-reactive. Appearance of TSG-14 protein was demonstrated in the serum of mice after injection with LPS. No TSG-14 mRNA was detected in the liver of LPS-injected mice, suggesting that hepatocytes are not the major site of TSG-14 synthesis. Thus, in the intact organism the main cellular sources of TSG-14 and classical acute phase proteins appear to be different.
 ...
PMID:Relationship of TSG-14 protein to the pentraxin family of major acute phase proteins. 752 2

Insulin treatment of the rat hepatoma H-35 cells results in a reduced stimulation of acute phase plasma protein gene expression by IL-1- and IL-6-type cytokines. The cell response to insulin appears to involve both stimulatory and inhibitory regulatory mechanisms because a clonal variant line of the H-35 cells has been identified in which insulin increases specifically the IL-1 stimulation of alpha 1-acid glycoprotein (AGP) gene, while still reducing the expression of the other acute phase protein genes. The magnitude of insulin and cytokine effect is dependent upon the proliferation state of the cell culture. One of the genetic targets of the insulin stimulation has been located to the cytokine-response element of the AGP gene and involves a cooperativity with the 5' adjacent IL-1-responsive element. The molecular mechanism of insulin inhibition, however, remains to be identified.
 ...
PMID:Insulin cooperates with IL-1 in regulating expression of alpha 1-acid glycoprotein gene in rat hepatoma cells. 753 58

The synthesis of the human acute-phase alpha 1-acid glycoprotein (AGP) is primarily controlled by IL-6 and IL-1 in liver cells. In the present study, monoclonal antibodies against human gp80 interleukin-6 receptor (IL-6R) were utilized to study the role of the IL-6R in the control of the IL-6-induced AGP synthesis in the human hepatoma Hep3B cell line. Two of the 4 MAbs used in this study, M164 and M195, identified 2 different epitopes involved in IL-6 binding and two others, M91 and M182, recognized epitopes not involved in IL-6 binding. Dose-response experiments indicated that up to 55% of AGP synthesis was inhibited by 10(5) ng/ml of MAbs 164 or 195 when Hep3B cells were treated by IL-6 for 48h. Kinetics of the inhibition of AGP synthesis after addition of anti-IL-6R indicated that the decrease of the IL-6-induced AGP synthesis by Hep3B cells was obtained immediately after the addition of the anti-IL-6R MAbs. Of the two MAbs not involved in IL-6 binding, M91 was unable to interfere with the IL-6-induced AGP synthesis whereas, surprisingly, M182 decreased it by about 25%. Since M182 was also able to interfere with the proliferative response of an IL-6 dependent plasma cell line, our results suggested that M182 may be directed to a structure involved in the IL-6/IL-6R gp130 complex formation.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:IL-6-induced changes in synthesis of alpha 1-acid glycoprotein in human hepatoma Hep3B cells are distinctively regulated by monoclonal antibodies directed against different epitopes of IL-6 receptor (gp80). 753 7

This study assessed the hepatic acute phase response and cellular Ca2+ regulation in septic animals and in hepatoma cell lines in vitro. Sepsis was induced in male Sprague-Dawley rats by implanting in their abdominal cavities fecal pellets impregnated with live Escherichia coli and Bacteroides fragilis. 8 h after implantations, rats were treated with diltiazem (1.2 mg/kg) or superoxide dismutase (SOD) (5 x 10(3) units/kg). After 24 h, plasma acute phase proteins (APP) were determined by immunoelectrophoresis, and hepatic APP-mRNAs by Northern blot hybridization. Effects of diltiazem, verapamil, or SOD on hepatic cells were determined in rat Reuber H-35 and human HepG2 hepatoma cells. Sepsis induced a significant increase in plasma APP and their hepatic mRNAs. Diltiazem and SOD reduced the sepsis-induced elevations in plasma lactate, the febrile response and mortality. APP expression in H-35 and HepG2 cells, stimulated by interleukin 1 (IL-1), IL-6, and dexamethasone, was inhibited by diltiazem or verapamil but not SOD. The results suggest that a heightened hepatic APP response in septic animals accompanies systemic/metabolic derangements and a significant animal mortality. Because diltiazem was previously shown to prevent sepsis-related disturbances in hepatic cellular Ca2+ regulation, its mediation of decrease in APP, systemic/metabolic response, and mortality may be effected through modifications in cellular Ca2+ regulation. The data from hepatoma cells show an attenuation of the AAP can result from direct effects of a calcium blocker. However, whether the blocker primarily modifies cellular Ca2+ regulation and secondarily effects APP gene expression, or directly effects gene expression remains unknown.
 ...
PMID:Diltiazem and superoxide dismutase modulate hepatic acute phase response in gram-negative sepsis. 753 32

Acute inflammation is characterized by increased production of acute phase proteins in the liver. The induction of the hepatocytic response is primarily mediated through soluble cytokines such as IL-1, IL-6, TNF-alpha, and transforming growth factor beta, which bind to specific cell surface receptors and regulate gene expression of acute-phase proteins. Hepatoma cell lines, such as HepG2, represent a model system for studying acute-phase protein synthesis. HepG2 is induced to produce a variety of acute-phase proteins, including alpha 1-antitrypsin, alpha 1-antichymotrypsin, fibrinogen, alpha 1-acid glycoprotein, and haptoglobin, upon stimulation with cytokines. Analysis of HepG2 by reverse transcriptase PCR indicated that this cell line synthesized mRNA specific for the human C5a receptor (CD88). Flow cytometric analysis of HepG2 cells indicated that these cells bound anti-CD88 Ab, thus confirming our RT-PCR data by demonstrating that these cells also express the C5a receptor. Because C5a has been shown to be a potent mediator of inflammation and HepG2 cells express CD88, we assessed the possibility that C5a was capable of stimulating acute-phase protein synthesis by HepG2 cells. The results indicate that binding of human C5a to CD88 on HepG2 cells resulted in an increased production of alpha 1-antitrypsin- and alpha 1-antichymotrypsin-specific mRNA as assayed by RT-PCR. Analysis of culture supernatants derived from C5a-stimulated HepG2 cells showed an increased production of alpha 1-antitrypsin as measured by solid-phase ELISA. alpha 1-antitrypsin production by HepG2 cells was a direct result of C5a stimulation as evidenced by the fact that anti-C5a receptor Ab inhibited the response. These results suggest that C5a may be an important mediator of APP production in the regulation of the inflammatory response.
 ...
PMID:Expression of functional receptors for human C5a anaphylatoxin (CD88) on the human hepatocellular carcinoma cell line HepG2. Stimulation of acute-phase protein-specific mRNA and protein synthesis by human C5a anaphylatoxin. 754 17

The role of an androgen, dehydroepiandrosterone (DHEA) has been studied on the constitutive and IL-6 induced fibrinogen production of HepG-2 cells. DHEA markedly augments the constitutive fibrinogen production of the hepatoma cells in a dose dependent fashion. Oppositely, for IL-6 induced fibrinogen production, DHEA is strongly inhibitory. The effectiveness of DHEA on the constitutive fibrinogen production is further potentiated if the hepatoma cells are preincubated with a glucocorticosteroid, dexamethasone. These findings demonstrate that the complex interaction between the steroid- and cytokine-directed regulation of the production of acute phase proteins is further coloured by the action of androgens on immune and hormonal systems.
 ...
PMID:Dehydroepiandrosterone modulates the spontaneous and IL-6 stimulated fibrinogen production of human hepatoma cells. 755 18

Recently, a novel cytokine, cardiotrophin-1 (CT-1), was cloned and found to induce cardiac myocyte hypertrophy in vitro. Amino acid sequence similarity showed CT-1 to be a member of the IL-6/LIF/CNTF/OSM/IL-11 cytokine family. Since all known members of the IL-6 cytokine family induce an hepatic acute phase protein (APP) gene expression, we investigated the ability of CT-1 to induce a liver acute phase response. Upon stimulation of rat hepatoma cells, CT-1 and LIF induced the strongest rat fibrinogen mRNA expression, OSM and IL-6 induced a less pronounced response. When human hepatoma cells and primary rat hepatocytes were stimulated with CT-1, the expression of human haptoglobin and rat alpha 2-macroglobulin mRNA was induced. The induction of the acute phase response was dose- and time-dependent. In this study we demonstrate that CT-1, a novel cytokine belonging to the IL-6 cytokine family, is a hepatocyte stimulating factor.
 ...
PMID:A new hepatocyte stimulating factor: cardiotrophin-1 (CT-1). 755 64

Mutagenesis of a region of human interleukin (IL)-6 which is important for triggering signal transduction via the IL-6 receptor beta-chain (gp130) has lead to the isolation of a variant of human IL-6 (IL-6.Q160E/T163P), which could antagonize the biological activity of wild type IL-6 on the human EBV transformed B cell line CESS and the human hepatoma cell line HepG2. Surprisingly this antagonistic IL-6 variant had an agonistic effect on the human myeloma cell line XG-1, albeit at a 1000-fold higher concentration than wild type IL-6. This residual activity of the mutant arose from triggering gp130, because it could be inhibited by a gp130 specific mAb. Extensive mutagenesis of residues between Q153 and H165 of human IL-6, a region which is partly homologous in cytokines which also signal via gp130 (oncostatin M, ciliary neurotrophic factor, leukaemia inhibitory factor, IL-11), did result in the isolation of a second antagonist for IL-6 activity on CESS and HepG2 cells. However on XG-1 cells this variant was active as well. These results suggest that (an) additional region(s) of the IL-6 molecule might be involved in gp130 triggering. Recently we indeed found that residues Lys42-Ala57 are also important for gp130 triggering. Inhibition experiments with neutralizing IL-6R alpha-chain specific mAb show that this region can be functionally separated from the Q153-H165 region. These findings have important implications for the development of receptor antagonists of IL-6 and IL-6 family members.
 ...
PMID:Functional distinction of two regions of human interleukin 6 important for signal transduction via gp130. 757 77


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>