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)

A transgenic mouse model for hepatocarcinoma has been previously produced by targeting SV40 T-antigen expression to the liver. To evaluate the perturbation of cell death occurring during hepatocarcinogenesis, we examined the Fas-induced apoptosis on hepatocytes expressing T-antigen. Whereas anti-Fas antibody induced apoptosis in primary cultured normal hepatocytes, they imparted a weak cytotoxicity on primary cultured hepatocytes expressing T-antigen. This resistance of hepatic Fas-mediated apoptosis appears to result in an enhancement of a protective mechanism involving the protein kinase C signaling pathway rather than in a down-regulation of Fas-antigen expression. We further demonstrated that anti-Fas antibody does not have as efficient a lethal effect in T-antigen transgenic mice as in wild-type mice. The livers of transgenic mice injected with anti-Fas mAbs showed large intact regions with a few scattered apoptotic bodies: these regions strictly corresponded with carcinoma nodules, expressing high level of T-antigen. Our results describe a novel function for SV40 T-antigen which could contribute to viral pathogenesis by protecting infected cells against the host apoptotic defense mechanism.
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PMID:Fas-dependent apoptosis is impaired by SV40 T-antigen in transgenic liver. 756 65

Heme-hemopexin or cobalt protoporphyrin (CoPP)-hemopexin (a model ligand for hemopexin receptor occupancy) is shown to increase transcription of the metallothionein-1 (MT-1) gene by activation of a signaling pathway. Promoter deletion analysis followed by transient transfection assays show that 110 base pairs (-153 to -43) of 5'-flanking region of the murine MT-1 promoter are sufficient for increasing transcription in response to heme-hemopexin or to CoPP-hemopexin in mouse hepatoma cells. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), prevented the increase in MT-1 transcription by heme-hemopexin, CoPP-hemopexin, or phorbol 12-myristate 13-acetate, but the protein kinase A inhibitor, HA1004, was without effect. N-Acetylcysteine (NAC) and glutathione, as well as superoxide dismutase and catalase, inhibited both the increase in endogenous MT-1 mRNA and the activation of reporter gene activity by heme-hemopexin, CoPP-hemopexin, and phorbol 12-myristate 13-acetate. In sum, these data suggest that reactive oxygen intermediates are generated by heme-hemopexin via events associated with receptor binding, including protein kinase C activation. Induction of heme oxygenase-1 expression, in contrast to MT-1, is significantly less sensitive to NAC. Deletion and mutation analyses of the MT-1 proximal promoter revealed that the sequence 5'-GTGACTATGC-3' (from -98 to -89 base pairs) is, in part, responsible for the hemopexin-mediated regulation of MT-1 which is inhibited by H7. Regulation via this element is also induced by H2O2 showing that it is an antioxidant response element. Heme itself acts via more distal elements on the MT-1 promoter. In contrast to NAC and glutathione, diethyl dithiocarbamate and pyrrolidine dithiocarbamate, which inactivate reactive oxygen intermediates and chelate Zn(II), synergistically augment the induction of MT-1 mRNA levels and reporter gene activity in response to heme-hemopexin via the antioxidant response element by both metal-responsive element-dependent and -independent mechanisms.
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PMID:Mechanism of metallothionein gene regulation by heme-hemopexin. Roles of protein kinase C, reactive oxygen species, and cis-acting elements. 759 95

Hepatic metabolism and gene expression are among the factors controlled by the cellular hydration state, which changes within minutes in response to aniso-osmotic environments, cumulative substrate uptake, oxidative stress and under the influence of hormones such as insulin. The signalling events coupling cell-volume changes to altered cell function were studied in H4IIE rat hepatoma cells. Hypo-osmotic cell swelling resulted within 1 min in a tyrosine kinase-mediated activation of the extracellular signal-regulated protein kinases Erk-1 and Erk-2, which was independent of protein kinase C and cytosolic calcium. Activation of mitogen-activated protein kinases was followed by an increased phosphorylation of c-Jun, which may explain our recently reported finding of an about 5-fold increase in c-jun mRNA level in response to cell swelling. Pretreatment of cells with pertussis or cholera toxin abolished the swelling-induced activation of Erk-1 and Erk-2, suggesting the involvement of G-proteins. Thus, a signal-transduction pathway resembling growth factor signalling is activated already by osmotic water shifts across the plasma membrane, thereby providing a new perspective for adaption of cell function to alterations of the environment.
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PMID:Activation of extracellular signal-regulated kinases Erk-1 and Erk-2 by cell swelling in H4IIE hepatoma cells. 761 47

Specific cellular sites of action of the environmental pollutant, lead, have not been completely defined. The present investigations were conducted to test the hypothesis that lead exposure perturbs glucocorticoid-mediated effects in hormonal target tissues. The cell culture model chosen for these investigations was the effects of lead on glucocorticoid-regulated tyrosine aminotransferase (TAT) specific activity in the H4-II-C3 hepatoma cells. Cells were treated with 300 nM-10 microM lead acetate for 24 or 48 h in absence or presence of the inducing agent, dexamethasone. Lead dose-dependently inhibited TAT specific activity up to 52% and 61% following 24 and 48 h lead treatments, respectively. These treatment times and concentrations of lead acetate did not significantly alter total cell numbers, [3H]thymidine incorporation or trypan blue exclusion. Glucocorticoid receptor-binding studies yielded a Kd = 8.3 nM and a Bmax = 290 fmol/mg protein in untreated cells versus a Kd = 9.2 nM and Bmax = 262 fmol/mg protein in cells exposed to 10 microM lead acetate for 48 h. Treatment with lead did not significantly perturb uptake of the inducing glucocorticoids or initial cytosolic receptor-binding events. To sustain induced levels of TAT, glucocorticoid must be continuously present. Following steroid withdrawal, enzyme de-induction was significantly altered in lead-treated cells. At 6 h following dexamethasone withdrawal, TAT levels had decreased to 51% of maximum in sodium acetate-treated cells. This was significantly reduced to 33% of maximum in lead acetate-treated cells. Lead treatment of HTC cells was also shown to ameliorate PMA amplification of dexamethasone-induced TAT activity. Taken together, these results suggest that acute exposure of cells to lead may inhibit processes involved in glucocorticoid-mediated enzyme induction within the hormonal target cell. Results suggest that lead may be acting to increase the turnover of TAT by actions at the transcription, translation and/or posttranslational level. Lead may also be affecting PKC-mediated phosphorylations in the glucocorticoid-TAT signal transduction system.
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PMID:The acute effect of lead acetate on glucocorticoid regulation of tyrosine aminotransferase in hepatoma cells. 762 83

We compared the influence of exogenous N-ras oncogene and treatment with PKC agonist 12-O-tetradecanoylphorbol-13-acetate (TPA) on P-glycoprotein (Pgp) function in various human, rat and dog cell lines. Two approaches were used: (a) flow cytometry analysis of Rhodamine 123 (Rh123) exclusion; and (b) sensitivity to cytotoxic action of colchicine. We have found that in Rat1 fibroblasts, rat IAR2 epithelial cells and rat McA RH 7777 (hepatoma), ras activates Pgp function, while in MDCK (dog kidney), K562 (human chronic myelogenous leukaemia) and LIM1215 (human colon carcinoma) cells it either has no effect or even acts in opposite direction. TPA-induced Pgp function shows dissimilar pattern of cell specificity. It is assumed that PKC and ras oncogene regulate mdr1 gene expression through at least partially distinct signalling pathways.
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PMID:Cell-specific effects of RAS oncogene and protein kinase C agonist TPA on P-glycoprotein function. 762 41

Rats fed a choline deficient diet develop foci of enzyme-altered hepatocytes with subsequent formation of hepatic tumors. This is the only nutritional deficiency that, in itself, causes cancer. We suggested that carcinogenesis is triggered, in part, because of abnormalities in cell signals which regulate cell proliferation and cell death. Because choline deficient rats develop fatty liver (choline is needed for hepatic secretion of certain lipoproteins), we examined whether an important lipid second messenger involved in proliferative signaling, 1,2-sn-diacylglycerol, accumulated in liver and resulted in the prolonged activation of protein kinase C. We observed that 1,2-sn-diacylglycerol accumulated in the plasma membrane from the non-tumor portion of livers of rats fed a choline deficient diet, and that unsaturated free fatty acids, another activator of protein kinase C, also accumulated in deficient livers. Protein kinase C in the hepatic plasma membrane and nucleus of choline deficient rats was elevated for months; this is the only model system which exhibits such prolonged activation of protein kinase C. Premalignant, abnormal hepatic foci were detected only in the deficient rats, and 15% of deficient rats (none of the controls) had hepatocellular carcinoma at 1 year on the diet. In rats, an early event in choline deficiency is an increase in the rate of cell death. In liver from choline deficient rats, we observed an increase in the numbers of liver cells with fragmented DNA (characteristic of programmed cell death; apoptosis). We used a cell culture model (immortalized rat hepatocytes) to study the effects of choline deficiency on apoptosis. Liver cells grown in a choline deficient medium became depleted of choline, accumulated triacylglycerol and 1,2-sn-diacylglycerol, and had increased DNA fragmentation and other morphologic and biochemical changes associated with apoptosis. This model has great potential as a tool for studying the underlying link between choline deficiency and the regulation of the balance between cell proliferation and cell death. We suggest that choline deficiency altered the cell proliferation signals mediated by protein kinase C within liver, and altered cell apoptosis. These changes in cell signaling may be the triggering events which result in hepatic carcinogenesis.
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PMID:Choline and hepatocarcinogenesis in the rat. 764 29

The human hepatoma cell line, Hep 3B, produces biologically active erythropoietin (Epo) in response to normal physiologic stimuli and thus provides a model system for the study of Epo regulation. The addition of phorbol 12-myristate 13-acetate (PMA) to Hep 3B cells subsequently grown under hypoxic conditions resulted in a dose-dependent inhibition of hypoxia-induced Epo production by as much as 95 +/- 1% with half-maximal inhibition at 8 ng/mL. By Northern blot analysis, Epo mRNA levels were correspondingly decreased after treatment with PMA. Direct measurement of both membrane and cytosolic protein kinase C activity in Hep 3B cells following treatment with PMA demonstrated a biphasic response as a function of time. Membrane-associated protein kinase C activity initially increased but subsequently decreased to baseline levels by 12 hours. The PMA-induced inhibition of hypoxia-induced Epo production was shown to occur as early as 3 hours after PMA addition, suggesting that the initial activation, rather than the subsequent decrease in protein kinase C activity, is of primary importance. The relative specificity of the PMA-induced inhibition of Epo production was demonstrated by 1) the finding that overall protein and RNA synthesis were not similarly decreased as measured by 3H-leucine and 3H-uridine pulse labeling studies and 2) the observation that the biologically inactive phorbol ester, 4 alpha-phorbol didecanoate, failed to have any effect on hypoxia-induced Epo production. In addition, the synthetic analog of diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG) and the calcium ionophore, A23187, inhibited hypoxia-induced Epo production up to 85 +/- 3% and 82 +/- 4%, respectively, in a dose-dependent manner. Taken together, these findings suggest that hypoxia-induced Epo production may be negatively regulated by activators of a protein kinase C-mediated pathway.
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PMID:Modulators of protein kinase C inhibit hypoxia-induced erythropoietin production. 753 Feb 14

Treatment of murine hepatoma 1c1c7 cultures with dibenz[a,c]anthracene (DB[a,c]A)-induced P450 Cyp1a-1, as indicated by analyses of CYP1A1 mRNA and 7-ethoxyresorufin O-deethylase (EROD) activity. Pretreatment of cultures with 12-O-tetradecanoylphorbol-13-acetate (TPA) for as short as 1 h reduced protein kinase C (PKC) activity and resulted in a temporary suppression of EROD induction. The dose-response curves defining the TPA-dependent suppression of EROD induction and PKC down-regulation were very similar, as were the initial kinetics of PKC loss and the times of TPA pretreatment required for suppression of EROD induction. The effects of TPA could not be mimicked by 4 alpha-TPA, an analog incapable of activating and down-regulating PKC. Pretreatment of cultures with the protein kinase inhibitors staurosporine, calphostin C, or H7 resulted in dose-dependent suppressions of EROD induction. However, the suppressive and cytotoxic effects of these agents could be separated from one another in the case of only H7. HA1004, an analog of H7 that inhibits the same spectrum of protein kinases as H7 except for PKC, did not inhibit DB[a,c]A induction of EROD. Pretreatment of cultures with H7, but not HA1004, suppressed the accumulation of CYP1A1 mRNA that normally occurred following treatment with DB[a,c]A. Collectively, these studies suggest that PKC plays a role in the processes involved in the induction of Cyp1a-1.
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PMID:Suppression of cytochrome P450 Cyp1a-1 induction in murine hepatoma 1c1c7 cells by 12-O-tetradecanoylphorbol-13-acetate and inhibitors of protein kinase C. 768 64

Interleukin 6 is an important peptide regulatory factor with diverse biological activities including stimulation of acute phase protein synthesis. In this report we describe the effect of signal transduction pathway modulators on interleukin 6 mediated acute phase protein synthesis in a human hepatoma cell line Hep G2. Genistein, a tyrosine kinase inhibitor inhibited the interleukin 6 stimulated synthesis of acute phase proteins suggesting that a tyrosine kinase event participates in the signal transduction pathway. There was no evidence to suggest that protein kinase C had a stimulatory role although this or a related kinase may be involved in down-regulating the interleukin 6 signal.
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PMID:Interleukin 6 signal transduction in a human hepatoma cell line (Hep G2). 769 92

We investigated the effect of bile acids on major histocompatibility complex (MHC) class I gene expression in the cultured human hepatoma cell HepG2. Not only chenodeoxycholic acid, but its stereoisomer ursodeoxycholic acid as well, increased steady state level of MHC class I mRNA. When various bile acids were studied, inducibility of MHC class I mRNA was closely associated with the hydrophobicity of the corresponding bile acids. Pretreatment of the cells with a protein kinase C (PKC) inhibitor H7 suppressed induction of MHC class I mRNA by those bile acids. Furthermore, treatment of the cells with chenodeoxycholic acid significantly induced translocation of PKC from cytosol to membrane. In summary, our data strongly indicate up-regulatory effect of bile acids on MHC class I mRNA expression, most probably via activation of PKC-dependent pathway.
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PMID:Regulation of the major histocompatibility complex class I mRNA expression by bile acids in cultured human hepatoma cells. 770 23


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