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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Hepatocyte growth factor (HGF) stimulates inositol 1,4,5-trisphosphate (InsP3) formation in rat primary cultured hepatocytes, which is inhibited by the pretreatment with a tyrosine kinase inhibitor, genistein. This InsP3 production was coincident with tyrosine phosphorylation of phospholipase C gamma (PLC gamma), detected in immunoprecipitates with anti-PLC gamma, suggesting activation mechanism of PLC gamma by tyrosine phosphorylation. However, in human hepatocarcinoma HepG2 cells, HGF, which suppresses cell growth, causes neither phosphorylation of PLC gamma nor InsP3 formation. The results suggests that PLC gamma in normal hepatocytes was activated by HGF through tyrosine kinase of HGF receptor.
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PMID:Tyrosine phosphorylation of phospholipase C gamma in c-met/HGF receptor-stimulated hepatocytes: comparison with HepG2 hepatocarcinoma cells. 767 1

Activation of the insulin receptor tyrosine kinase is thought to initiate a chain of phosphorylation changes which regulate various metabolic and growth processes. Insulin has been shown to regulate some kinases by affecting their phosphorylation states; however, direct connections between activation of the receptor tyrosine kinase and subsequent altered phosphorylations of these kinases have yet to be established. To define the constituents of these regulated phosphorylation cascade systems, the time course of insulin-induced phosphorylation changes has been examined. 32P-Labeled H4IIE hepatoma cells were treated with insulin for 5-300 s, and then cell extracts were subjected to two-dimensional gel electrophoresis. Computer analysis of autoradiograms was employed to quantify insulin-induced phosphorylation changes. Phosphotyrosine was assessed by KOH digestion, by anti-phosphotyrosine immunoprecipitation, and by phenylarsine oxide treatment. Insulin induced a hierarchy of phosphorylation changes over the 300-s time course, with most increases being detectable within 10 s. Of these, only four did not undergo enhanced tyrosine phosphorylation. Eight proteins were found to undergo transient phosphorylation changes. Phenylarsine oxide elicited the appearance of novel low molecular weight phosphoproteins. These results support the concept of insulin-directed phosphorylation cascades, but indicate the magnitude of potential targets of the insulin receptor has been underestimated.
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PMID:Insulin regulation of protein phosphorylation in H4 hepatoma cells. Examination of rapid effects using two-dimensional electrophoresis. 768 56

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 had earlier reported that the human serum alpha 2-HS glycoprotein (1) is a physiological and specific inhibitor of the human insulin receptor tyrosine kinase (IR-TK). We have now expressed this human protein in the baculoviral expression system using the Sf-9 and High Five insect cells. The protein was optimally expressed at 72 h post infection. alpha 2-HSGbac completely inhibited the insulin-stimulated autophosphorylation and TK activity of partially purified IR preparations. It also abolished insulin-induced DNA synthesis in the H-35 rat hepatoma cell line. The effective concentration of the baculoviral derived alpha 2-HSG necessary for inhibiting IR-TK activity was significantly lower than that of the protein purified from human plasma.
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PMID:Baculoviral expression of a natural inhibitor of the human insulin receptor tyrosine kinase. 769 46

Previous studies have suggested that both cAMP-dependent signal transduction pathway and Ca2+/protein kinase C-dependent pathway are involved in GSH efflux from hepatocytes. In the present study, GSH efflux from Hep G2 cells, a human-derived hepatoma cell line, was further characterized. Both epidermal growth factor (0.1-10 ng/ml) and insulin (1 microgram/ml) significantly increased GSH efflux from Hep G2 cells. A fall in the membrane potential produced by the replacement of Na+ with equivalent K+ did not affect GSH efflux significantly. Neither ouabain, a Na+/K+ ATPase inhibitor, vanadate, a Ca2+ ATPase inhibitor, nor BaCl2, a K+ channel blocker, significantly affected the GSH efflux. Methionine (1mM) decreased GSH efflux from the cells, although total GSH content in the cells was not affected during the incubation time of 60 min. Signal transductions through tyrosine kinase-coupled receptors may also be involved in GSH efflux from hepatocytes.
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PMID:Characterization of glutathione efflux from Hep G2 cells. 782 1

In the present studies, insulin was found to stimulate in a rat hepatoma cell line (called FAO cells) the tyrosine phosphorylation of the 60-kilodalton p21ras GTPase-activating protein (GAP)-associated protein called p60. Surprisingly, the tyrosine phosphorylation of this protein was also almost equally stimulated by an activator of protein kinase C (PKC), the phorbol ester phorbol 12-myristate 13-acetate (PMA). The tyrosine phosphorylation of p60 induced by either agent correlated with the formation of the GAP-p60 complex in situ and an increase in the ability of p60 to directly bind to the SH2 domain of GAP in vitro. Several lines of evidence indicated that the PMA-induced tyrosine phosphorylation of p60 occurred through a different mechanism than that induced by insulin. First, the stimulation of tyrosine phosphorylation of p60 by maximal concentrations of the two agents was almost additive. Second, down-regulation of PKC or pretreatment with a specific inhibitor of PKC abolished the ability of PMA to stimulate tyrosine phosphorylation of p60 but had no effect on the insulin stimulation. And third, long-term pretreatment with insulin abolished the insulin response but did not affect the response to PMA. The PMA effect did seem to be mediated via a tyrosine kinase, since it was blocked by quercetin, an inhibitor of tyrosine kinases. These results indicate that both PMA and insulin can equally stimulate in FAO cells the tyrosine phosphorylation of p60 and its association with GAP, although these two agents seem to act via different signaling systems.
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PMID:Activation of protein kinase C stimulates the tyrosine phosphorylation and guanosine triphosphatase-activating protein association of p60 in rat hepatoma cells. 783 79

Considerable evidence has shown that most physiologic responses to insulin require activation of the intrinsic tyrosine kinase of the insulin receptor. Biochemical studies have also supported the hypothesis that receptor kinase activity can be modulated by cellular protein tyrosine phosphatases (PTPases), which have not yet been identified. To test the hypothesis that the transmembrane PTPase LAR can modulate insulin receptor signaling in vivo, antisense RNA expression was used to specifically suppress LAR protein levels by 63% in the rat hepatoma cell line, McA-RH7777. Hormone-dependent autophosphorylation of the insulin receptor was increased by approximately 150% in the antisense-expressing cells at all insulin concentrations tested. This increase in autophosphorylation was paralleled by a 35% increase in insulin receptor tyrosine kinase activity. Reduced LAR levels did not alter non-hormone-dependent tyrosine phosphorylation nor basal insulin receptor tyrosine phosphorylation and kinase activity. Most significantly, reduced LAR levels resulted in a 350% increase in insulin-dependent phosphatidylinositol 3-kinase activity. These studies provide unique in vivo evidence that LAR is involved in the modulation of insulin receptor signaling in intact cells.
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PMID:Insulin receptor signaling is augmented by antisense inhibition of the protein tyrosine phosphatase LAR. 785 2

Altered expression of protooncogenes/oncogenes is believed to be involved in hepatocarcinogenesis of the chemically induced, transplantable Morris hepatoma 7777. We compared the mRNA expression of c-N-ras and v-erb B mRNA of normal rat liver with that of Morris hepatoma 7777 using Northern blot analysis and in situ hybridization. Northern blot analysis revealed a strong overexpression of the v-erb B related mRNA, while the c-N-ras mRNA was only slightly increased. In situ hybridization using a c-N-ras mRNA probe also showed only a slightly increased number of silver grains in the hepatoma cells compared with normal rat liver. On the other hand, the v-erb B related mRNA was strongly overexpressed in the hepatoma cells, while the connective-tissue capsule, the blood vessels, blood cells and the necrotic foci did not show an elevated v-erb B related gene mRNA expression. Similar results were obtained in liver metastases. The detectable v-erb B hybridization signal was lost by pretreatment with RNase A. We conclude that the c-N-ras gene is of minor importance in the chemically induced, transplantable Morris hepatoma 7777, while the increased expression of the v-erb B related mRNA is due to a selection of ligand-independent tyrosine kinase activity.
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PMID:Expression of the erb B oncogene in the Morris hepatoma 7777. 786 26

Insulin rapidly stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of the cytosolic substrate, insulin receptor substrate-1 (IRS-1), which, in turn, associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. In the present study we have examined these three early postreceptor components of the insulin action pathway in rat hepatoma (Fao) cells and have determined the effects of two hormones that can induce insulin resistance, dexamethasone and insulin. Dexamethasone (1 microM) induced a time- and dose-dependent increase in insulin receptor levels in Fao cells, reaching 135 +/- 3% of basal levels after 24 h (P < 0.05). There was a simultaneous increase in IRS-1 protein to 255 +/- 66% of the control value (P < 0.05) and a parallel increase in IRS-1 phosphorylation. Insulin stimulation of IRS-1-associated PI 3-kinase was also increased by 70% in cells treated with dexamethasone despite only a minimal increase in PI 3-kinase protein, as determined by immunoblotting. Prolonged insulin treatment induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels, reaching nadirs of 40 +/- 4% (P < 0.01) and 15 +/- 6% (P < 0.005) of control levels, respectively, after 24 h with 100 nM insulin. There was also a decrease in the phosphorylation of insulin receptors and IRS-1, a marked decrease in the association between IRS-1 and PI 3-kinase, and an 82% decrease in insulin-stimulated PI 3-kinase activity without a significant change in PI 3-kinase protein levels. When cells were exposed to both insulin and dexamethasone, the effect of insulin to reduce insulin receptor and IRS-1 levels and insulin-stimulated IRS-1 phosphorylation dominated. These data suggest that regulation of the insulin receptor, IRS-1, and PI 3-kinase contributes significantly to the insulin resistance induced by chronic hyperinsulinemia, but that glucocorticoid-induced insulin resistance is located beyond these early steps in insulin action.
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PMID:Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. 789 67


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