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)

Epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) synergistically suppress activities of the promoter and enhancer of the human alpha-fetoprotein (AFP) gene in HuH-7 human hepatoma cells as analyzed by transient transfection assays using the chloramphenicol acetyltransferase gene as a reporter. In contrast to the AFP gene, albumin promoter and enhancer activities were not affected by EGF and TPA. Unexpectedly, however, Northern blot analysis revealed that the albumin mRNA level as well as the AFP mRNA level were reduced by treatment with EGF and TPA. We propose that in HuH-7 cells, the AFP enhancer stimulates the albumin promoter as well as the AFP promoter; and consequently, inhibition of the AFP enhancer by EGF and TPA results in reduction of both AFP and albumin mRNA levels. The significance of the involvement of the AFP enhancer in albumin transcription is discussed in relation to the inverse pattern of expression of the AFP and albumin genes in neonatal growth.
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PMID:A possible mechanism of inverse developmental regulation of alpha-fetoprotein and albumin genes. Studies with epidermal growth factor and phorbol ester. 137 Apr 67

Prolactin (PRL) and insulin-like growth factor-binding protein (IGFBP-1) are two major secretory proteins of human endometrial/decidual cells. We have characterized the mRNA of PRL and IGFBP-1 and studied the effect of progestin, medroxyprogesterone acetate (MPA), anti-progestin (RU486), and relaxin (RLX) on the levels of these two mRNA transcripts in a long-term culture of human endometrial stromal cells. Northern blot analysis showed that the size of PRL mRNA was 1.15 kb and that of IGFBP-1 mRNA, 1.6 kb. Primer extension of endometrial/decidual IGFBP-1 mRNA showed two transcription initiation sites identical to those found in HepG2 human hepatoma cell line. The levels of mRNA in control samples remained low, approximately 2 pg PRL and approximately 5 pg IGFBP-1/microgram RNA at various times of culture. When stromal cells were treated with MPA for 28 days, PRL mRNA gradually increased 100-fold whereas IGFBP-1 mRNA exponentially increased approximately 1000-fold compared to control values and leveled after 25 days in culture. The timing of maximal stimulation was shortened by withdrawing MPA or by replacing MPA with RU486. After removal of MPA, levels of both mRNAs increased and each peaked after approximately 10 days, with PRL showing a 2-fold and IGFBP-1 a 20-fold increase compared to cells treated with MPA continuously. Replacing MPA by RU486 caused a rapid increase of PRL mRNA (2-3-fold) in 2-3 days followed by a gradual reduction to less than 20% of peak levels over the next 3 days. IGFBP-1 mRNA levels increased 30- and 100-fold in 1-2 days followed by a reduction to less than 20% of peak levels over the next 24 h. The reduction of mRNA levels by RU486 was reversed when cells were rechallenged with MPA. Relaxin alone caused a transient stimulation of PRL and IGFBP-1 mRNA. Maximal stimulation occurred between 10 and 20 days of culture and was 100-fold for PRL and 1000-fold for IGFBP-1 relative to control values. Cells treated with MPA and RLX in sequence had higher mRNA levels than cells treated with MPA continuously or cells subjected to MPA withdrawal. Maximal mRNA levels reached 0.4 ng PRL and approximately 8 ng IGFBP-1/microgram total RNA, approximately 0.04% and 0.8% of cellular RNA. The mRNA levels under various hormonal manipulations were similar to the previously published synthesis and secretion patterns of PRL and IGFBP-1 proteins in this system.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of progestin, antiprogestin, and relaxin on the accumulation of prolactin and insulin-like growth factor-binding protein-1 messenger ribonucleic acid in human endometrial stromal cells. 138 Aug 42

1. The induction of metallothionein (MT) protein by TPA (O-tetradecanoyl phorbol acetate), a protein kinase C activator, was demonstrated in vivo in rat liver and in vitro in rat hepatocytes in primary culture. In vivo half maximal induction at 25 hr was seen at 26 nmol TPA/kg body wt. Five- to seven-fold inductions were seen in vivo. De novo protein synthesis was required for this induction as demonstrated by cycloheximide inhibition of [35S]cysteine incorporation into MT protein. 2. TPA induction of MT protein in primary cultures of rat hepatocytes reached levels of 2.6-4.1-fold, as assessed by [35S]cysteine incorporation, 1.34-2.20-fold, as assessed by 109Cd binding in a metal displacement/HPLC assay, and 2.5-5-fold, as assessed by 109Cd binding in a metal displacement/Sephadex G-75 Superfine assay. 3. The induction of MT mRNA by TPA was demonstrated in vivo in rat liver and in vitro in 2 rat hepatoma cell lines, EC3 and 2M. MT mRNA was quantitated using dot blot and Northern gel assays. In vivo TPA induced hepatic MT mRNA 2.36-5.88-fold (dot blot) and 7.4-22-fold (Northern gels). In vitro TPA induced MT mRNA 1.71-15.26-fold in EC3 cells and 2.23-8.43-fold in 2M cells. MT mRNA was 0.54 kb, and alpha-tubulin mRNA was 1.62 kb in size on Northern gels. 4. TPA induction of MT protein and mRNA in vivo and in vitro is rapid and persistent and occurs at low concentrations. The 2 rat hepatoma cell lines provide a useful system in which to study MT induction in vitro without confounding secondary effects which can occur in vivo.
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PMID:Phorbol ester induction of rat hepatic metallothionein in vivo and in vitro. 139 94

Transforming growth factor-beta (TGF-beta) modulates some components of the acute phase response in hepatic cells. The mechanisms for these actions of TGF-beta are largely unknown. The authors recently found that the decrease in albumin mRNA after TGF-beta 1 treatment required de novo RNA and protein synthesis, suggesting that TGF-beta acts through induction of another gene. The purpose of the current study was to determine whether TGF-beta 1 could regulate the expression of both the jun and fos genes that encode transcriptional regulatory proteins that constitute the AP-1 complex, and to determine whether expression of these genes may be coordinated with the decrease in albumin mRNA. Northern blot hybridization was used to determine levels of specific mRNAs. Transforming growth factor-beta 1 increased the levels of both jun-B and fos-B mRNA by 60 minutes after treatment of mouse hepatoma (BWTG3) cells. When TGF-beta 1 was removed from the media after 4 hours, there was a sustained effect of increased jun-B and decreased albumin mRNA (greater than 48 hours), and the subsequent decrease in jun-B levels coincided with the increase in albumin mRNA. The tumor-promoting phorbol ester (phorbol 12-myristate 13-acetate [PMA]), known to induce jun and fos gene expression, caused increases in jun-B and fos-B that preceded the decrease in albumin mRNA levels at 24 hours. These observations are consistent with our hypothesis that jun-B and fos-B induction may participate in downregulation of albumin synthesis as well as other hepatic responses to TGF-beta.
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PMID:Transforming growth factor (TGF)-beta stimulates hepatic jun-B and fos-B proto-oncogenes and decreases albumin mRNA. 141 79

Receptor-mediated endocytosis via coated pits is modulated by the activity of protein kinases and protein phosphorylation. We examined the effects of the potent protein kinase inhibitor staurosporine (SSP) on endocytosis of the asialoglycoprotein (ASGP) receptor in HepG2 cells. Staurosporine caused a rapid (< 2 min) inhibition of ligand internalization from the cell surface. In contrast the rate of receptor exocytosis from intracellular compartments to the cell surface was not altered (t1/2 = 8 min). This resulted in increased ASGP receptors at the plasma membrane (140% of control) while the total number of receptors per cell was unchanged. Receptor up-regulation was half-maximal at 30 nM SSP. At this concentration staurosporine also inhibited the internalization of iodinated transferrin by HepG2 cells and SK Hep-1 cells, another human hepatoma-derived cell line. Staurosporine was without effect on the non-receptor-mediated uptake of Lucifer yellow by pinocytosis. We investigated the possible involvement of protein kinase C in the inhibitory effects of staurosporine on receptor endocytosis. The active protein kinase C inhibitor H7 did not inhibit ASGP receptor internalization. Furthermore depletion of cellular protein kinase C by overnight incubation with 1 microM phorbol myristate acetate did not abrogate the SSP effect. Together these data suggest that the mechanism of SSP action is independent of the inhibition of protein kinase C. In conclusion staurosporine is a potent and rapid inhibitor of receptor trafficking which is specific for receptor internalization from the plasma membrane.
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PMID:The effect of staurosporine, a protein kinase inhibitor, on asialoglycoprotein receptor endocytosis. 145 3

Results from nuclear run-off assays show that exposure of hepatocytes and Reuber H35B hepatoma cells to the tumour promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), leads to enhanced transcription of c-Ki-ras gene. This increase in transcription in turn results in an accumulation of the functionally active c-Ki-ras message. The half life of c-Ki-ras message in both normal and transformed livers cells is not altered by TPA and is determined to be 3.5 hr. The induction of c-Ki-ras message is accompanied by an increase in the level of c-Ki-ras protein.
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PMID:Transcription induction of c-Ki-ras with the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in normal and transformed liver cells. 148 Jan 66

The synthesis and secretion of apolipoprotein (apo) E, a major protein component of very low density lipoproteins, were examined in the human hepatoma cell line HepG2 under metabolic conditions known to stimulate lipogenesis and the production of apoB-containing lipoproteins. When HepG2 cells were incubated in the presence of fetal bovine serum (5 or 10%) or canine chylomicron remnants (5 or 10 micrograms of protein), the secretion of triglycerides and cholesteryl esters of lipoproteins of d less than 1.063 g/ml increased, as determined by the incorporation of [14C]acetate. Determination of the distribution of apoE among media lipoproteins by agarose column chromatography showed that the majority of secreted apoE was associated with large lipoproteins when cells were incubated with fetal bovine serum. However, immunoblot analysis of total media apoE revealed that incubating cells with or without the lipogenic factors had no effect on the amount of apoE secreted. Pulse-chase and continuous labeling experiments demonstrated that the synthesis and secretion of apoE did not vary under the different metabolic conditions, even though there was a 5-fold increase in apoB secretion in response to increased lipogenesis. Neither apoE nor apoB mRNA levels responded to the lipogenic stimuli. We conclude that the synthesis and secretion of apoE are independent of the production of apoB-containing lipoproteins in HepG2 cells.
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PMID:Synthesis and secretion of apolipoprotein E occur independently of synthesis and secretion of apolipoprotein B-containing lipoproteins in HepG2 cells. 155 3

One of insulin's actions is the induction of DNA synthesis and cell division, but little is known about the molecular mechanisms involved. Previous studies indicate that insulin stimulates cell division and regulates the expression of several genes in rat H4IIE (H4) hepatoma cells. One of these genes is the proto-oncogene c-fos, a cellular gene whose deregulation has been implicated in the process of cellular differentiation and division. We have shown that insulin induces transcription of the c-fos gene in H4 cells. In the present study, the phorbol ester, phorbol 12-myristate 13-acetate (PMA), stimulated c-fos transcription in a rapid and dose-dependent manner with an 800% increase in transcription following 15-30 min of addition. This increase in c-fos transcription was transitory, returning towards baseline transcription rates within 120 min. PMA stimulated the translocation of protein kinase C (PKC) from the cytoplasm to the membrane in H4 hepatoma cells, as evidenced by a 77% decrease in cytosolic PKC and a 29% increase in membrane PKC activity following 10 min of treatment. Insulin addition to H4 cells for 10 min also resulted in a 31% decrease in cytosolic PKC activity, suggesting a translocation response. When H4 cells were pretreated with PMA for 24 h, there was a decrease of 20-45% in both cytosolic and membrane PKC activity and a complete loss of PMA's induction of c-fos transcription. Thus, the cells were functionally desensitized to further PMA addition. When cells were pretreated with PMA for 24 h, the insulin-induced increase in transcription of c-fos was reduced by 50%. Western blot analysis indicated that the PKC-beta isozyme followed a translocation pattern almost identical with that of total PKC activity. These results suggest that a PMA-sensitive form of PKC is preferentially lost upon PMA pretreatment and that this PKC subtype may be necessary for insulin to fully induce c-fos gene expression.
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PMID:Role of protein kinase C in insulin's regulation of c-fos transcription. 157 56

Glucocorticoids induced ADH activity and mRNA 2- to 4-fold in rat hepatoma cells (H4IIE and H4IIEC3), but were reported not to alter ADH activity in rat liver. The failure of corticosteroids to induce ADH may have been due to the short-term treatment of the rats or the dose of steroid used. To reevaluate the effect of glucocorticoids in vivo, we studied animals 4.5 weeks after adrenalectomy so that ADH activity and mRNA should have reached a new steady-state level; the dose of glucocorticoid used was estimated to provide physiological replacement. Male Wistar rats were injected with a single daily dose (10 mg/kg/day) of corticosterone-21-acetate or vehicle subcutaneously for 10 days. Liver extracts were assayed for ADH activity, ADH protein, and ADH mRNA. Nuclei were isolated for nuclear run-on assays. Adrenalectomy did not reduce the activity of ADH in liver. Subsequent corticosterone treatment did not alter ADH enzyme activity, nor did it affect ADH protein levels as analyzed on Western blots. However, Northern blot analysis of ADH mRNA indicated a 2-fold increase in ADH mRNA in the treated animals when the data were normalized to the level of the 28S ribosomal RNA or CHO-B mRNA. The rate of transcription of the ADH gene in nuclei isolated at the end of 10 days of treatment from corticosterone-treated adrenalectomized rats was not statistically different from that in the oil-treated adrenalectomized ones. The disparity between ADH activity and protein levels and the mRNA level may have resulted from other effects of corticosterone, e.g., stimulation of protein degradation or effects on translation.
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PMID:Corticosterone induces rat liver alcohol dehydrogenase mRNA but not enzyme protein or activity. 162 40

The comparative effects of simvastatin (a competitive inhibitor of HMG-CoA reductase) and ciprofibrate (another inhibitor of cholesterogenesis) on the incorporation of [14C]acetate and [3H]mevalonate into cholesterol HMG-CoA reductase activity, apo-B synthesis, LDL receptor, and their corresponding mRNAs, have been studied in the human hepatoma cell line Hep G2 and in human and rat hepatocytes in primary culture. Incubation of Hep G2 with simvastatin (0.01-1.5 microM) or ciprofibrate (25-100 microM) produced not only a marked inhibition of cholesterogenesis from [14C]acetate but also from [3H]mevalonate, an intermediate downstream of the HMG-CoA reductase reaction. However, in human and rat hepatocytes, cultured in similar conditions, simvastatin inhibited only the cholesterol synthesis from [14C]acetate, as expected. HMG-CoA reductase activity was greatly induced in Hep G2 and rat hepatocytes after incubation with simvastatin (up to 400% of controls), but not with ciprofibrate. Increased enzyme activity was accompanied by a higher cell content of reductase mRNA. Apo-B concentration in the medium of Hep G2 cells was 31% lower after 31 h incubation with simvastatin than in controls. However, neither simvastatin nor ciprofibrate modified the synthesis rate of apo-B or its mRNA level. Both LDL-receptor and its mRNA levels were raised by simvastatin at concentrations inhibiting cholesterol synthesis. Our data show that, in this human hepatoma cell line, HMG-CoA reductase competitive inhibition by simvastatin triggers a coordinate regulation of the expression of genes coding for reductase and LDL receptor but not for apo-B. Ciprofibrate, though efficient in inhibiting cholesterogenesis, did not induce the same regulatory reactions. The reason for this discrepancy is unknown.
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PMID:Regulation of HMG-CoA reductase, apoprotein-B and LDL receptor gene expression by the hypocholesterolemic drugs simvastatin and ciprofibrate in Hep G2, human and rat hepatocytes. 162 34


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